What formula is best for milk protein allergy

Food allergies can own rapid-onset (from minutes up to 2 hours), delayed-onset (up to 48 hours or even 1 week), or combinations of both, depending on the mechanisms involved. The difference depends on the types of white blood cells involved. B cells, a subset of white blood cells, rapidly synthesize and secrete immunoglobulin E (IgE), a class of antibody which bind to antigens, i.e., the foreign proteins. Thus, immediate reactions are described as IgE-mediated. The delayed reactions involve non-IgE-mediated immune mechanisms initiated by B cells, T cells, and other white blood cells.

Unlike with IgE reactions, there are no specific biomarker molecules circulating in the blood, and so, confirmation is by removing the suspect food from the diet and see if the symptoms resolve.[18]

IgE-mediated symptoms include: rash, hives, itching of the mouth, lips, tongue, throat, eyes, skin, or other areas, swelling of the lips, tongue, eyelids, or the whole face, difficulty swallowing, runny or congested nose, hoarse voice, wheezing, shortness of breath, diarrhea, abdominal pain, lightheadedness, fainting, nausea and vomiting. Symptoms of allergies vary from person to person and may also vary from incident to incident.[19] Serious harm regarding allergies can start when the respiratory tract or blood circulation is affected.

The previous can be indicated by wheezing, a blocked airway and cyanosis, the latter by feeble pulse, pale skin, and fainting. When these symptoms happen, the allergic reaction is called anaphylaxis.[19] Anaphylaxis occurs when IgE antibodies are involved, and areas of the body that are not in direct contact with the food become affected and show severe symptoms.[19][20] Untreated, this can proceed to vasodilation, a low blood pressure situation called anaphylactic shock, and extremely rarely, death.[6][20]

For milk allergy, non-IgE-mediated responses are more common than IgE-mediated.[21] The presence of certain symptoms, such as angioedema or atopic eczema, is more likely related to IgE-mediated allergies, whereas non-IgE-mediated reactions manifest as gastrointestinal symptoms, without skin or respiratory symptoms.[18][22] Within non-IgE cow’s milk allergy, clinicians distinguish among food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP) and food protein-induced enteropathy (FPE).

Common trigger foods for every are cow’s milk and soy foods (including soy baby formula).[22][23] FPIAP is considered to be at the milder finish of the spectrum, and is characterized by intermittent bloody stools. FPE is identified by chronic diarrhea which will resolve when the offending food is removed from the infant’s diet. FPIES can be severe, characterized by persistent vomiting, 1 to 4 hours after an allergen-containing food is ingested, to the point of lethargy. Watery and sometimes bloody diarrhea can develop 5 to 10 hours after the triggering meal, to the point of dehydration and low blood pressure. Infants reacting to cow’s milk may also react to soy formula, and vice versa.[23][24] International consensus guidelines own been established for the diagnosis and treatment of FPIES.[24]


Mechanisms

Conditions caused by food allergies are classified into three groups according to the mechanism of the allergic response:[25]

  • Non-IgE mediated – characterized by an immune response not involving IgE; may happen hours to days after eating, complicating the diagnosis
  • IgE-mediated (classic) – the most common type, manifesting as acute changes that happen shortly after eating, and may progress to anaphylaxis
  • IgE- and non-IgE-mediated – a hybrid of the above two types

Allergic reactions are hyperactive responses of the immune system to generally innocuous substances, such as proteins in the foods we eat.

Some proteins trigger allergic reactions while others do not. One theory is resistance to digestion, the thinking being that when largely intact proteins reach the little intestine the white blood cells involved in immune reactions will be activated.[26] The heat of cooking structurally degrades protein molecules, potentially making them less allergenic.[27] Allergic responses can be divided into two phases: an acute response that occurs immediately after exposure to an allergen, which can then either subside or progress into a «late-phase reaction,» prolonging the symptoms of a response and resulting in more tissue damage.[28][29]

In the early stages of acute allergic reaction, lymphocytes previously sensitized to a specific protein or protein part react by quickly producing a specific type of antibody known as secreted IgE (sIgE), which circulates in the blood and binds to IgE-specific receptors on the surface of other kinds of immune cells called mast cells and basophils.

Both of these are involved in the acute inflammatory response.[28] Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation, and smooth muscle contraction. This results in runny nose, itchiness, shortness of breath, and potentially anaphylaxis. Depending on the individual, the allergen, and the mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to specific body systems; asthma is localized to the respiratory system, while eczema is localized to the skin.[28]

After the chemical mediators of the acute response subside, late-phase responses can often happen due to the migration of other white blood cells such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial reaction sites.

This is generally seen 2–24 hours after the original reaction.[29] Cytokines from mast cells may also frolic a role in the persistence of long-term effects. Late-phase responses seen in asthma are slightly diverse from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils.[30]

Six major allergenic proteins from cow’s milk own been identified: αs1-, αs2-, β-, and κ-casein from casein proteins and α-lactalbumin and β-lactoglobulin from whey proteins. There is some cross-reactivity with soy protein, particularly in non-IgE mediated allergy. Heat can reduce allergenic potential, so dairy ingredients in baked goods may be less likely to trigger a reaction than milk or cheese.

For milk allergy, non-IgE-mediated responses are more common than IgE-mediated. The previous can manifest as atopic dermatitis and gastrointestinal symptoms, especially in infants and young children. Some will display both, so that a kid could react to an oral food challenge with respiratory symptoms and hives (skin rash), followed a day or two later with a flare up of atopic dermatitis and gastrointestinal symptoms, including chronic diarrhea, blood in the stools, gastroesophageal reflux disease (GERD), constipation, chronic vomiting and colic.[2]

Allergic reactions are hyperactive responses of the immune system to generally innocuous substances, such as proteins in the foods we eat.

Some proteins trigger allergic reactions while others do not. One theory is resistance to digestion, the thinking being that when largely intact proteins reach the little intestine the white blood cells involved in immune reactions will be activated.[26] The heat of cooking structurally degrades protein molecules, potentially making them less allergenic.[27] Allergic responses can be divided into two phases: an acute response that occurs immediately after exposure to an allergen, which can then either subside or progress into a «late-phase reaction,» prolonging the symptoms of a response and resulting in more tissue damage.[28][29]

In the early stages of acute allergic reaction, lymphocytes previously sensitized to a specific protein or protein part react by quickly producing a specific type of antibody known as secreted IgE (sIgE), which circulates in the blood and binds to IgE-specific receptors on the surface of other kinds of immune cells called mast cells and basophils.

Both of these are involved in the acute inflammatory response.[28] Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation, and smooth muscle contraction.

This results in runny nose, itchiness, shortness of breath, and potentially anaphylaxis. Depending on the individual, the allergen, and the mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to specific body systems; asthma is localized to the respiratory system, while eczema is localized to the skin.[28]

After the chemical mediators of the acute response subside, late-phase responses can often happen due to the migration of other white blood cells such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial reaction sites. This is generally seen 2–24 hours after the original reaction.[29] Cytokines from mast cells may also frolic a role in the persistence of long-term effects.

Late-phase responses seen in asthma are slightly diverse from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils.[30]

Six major allergenic proteins from cow’s milk own been identified: αs1-, αs2-, β-, and κ-casein from casein proteins and α-lactalbumin and β-lactoglobulin from whey proteins. There is some cross-reactivity with soy protein, particularly in non-IgE mediated allergy. Heat can reduce allergenic potential, so dairy ingredients in baked goods may be less likely to trigger a reaction than milk or cheese.

For milk allergy, non-IgE-mediated responses are more common than IgE-mediated. The previous can manifest as atopic dermatitis and gastrointestinal symptoms, especially in infants and young children. Some will display both, so that a kid could react to an oral food challenge with respiratory symptoms and hives (skin rash), followed a day or two later with a flare up of atopic dermatitis and gastrointestinal symptoms, including chronic diarrhea, blood in the stools, gastroesophageal reflux disease (GERD), constipation, chronic vomiting and colic.[2]


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 2017)
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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    Endocr Metab Immune Disord Drug Targets. 2014 Mar14(1):2-8.

  • Different gut microflora

  • If challenge is positive, out of a research setting sensitization tests may not be necessary.
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  • Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor skills, communication, and social development scores.

    For each outcome measured, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome [19]

  • Longo G, Barbi E, Berti I, et al. Specific oral tolerance induction in children with extremely severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008;121:343-347.
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  • Different growth patterns

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    Arch Dis Kid. 2007 Oct92(10):902-8.

  • Osborn DA, Sinn J; Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 2006 Oct 18(4):CD003664.

  • It should be performed with physician supervision regardless of food-specific IgE value.
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  • Yeung JP, Kloda LA, McDevitt J, et al; Oral immunotherapy for milk allergy. Cochrane Database Syst Rev. 2012 Nov 1411:CD009542. doi: 10.1002/14651858.CD009542.pub2.

  • Liao SL, Lai SH, Yeh KW, et al; Exclusive breastfeeding is associated with reduced cow's milk sensitization in early childhood.

    Pediatr Allergy Immunol. 2014 Aug25(5):456-61. doi: 10.1111/pai.12247.

  • Bloom KA, Huang FR, Bencharitiwong R, et al; Effect of heat treatment on milk and egg proteins allergenicity. Pediatr Allergy Immunol. 2014 Dec25(8):740-6. doi: 10.1111/pai.12283. Epub 2014 Dec 18.

  • Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001: 107: 891-6
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  • Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120:1172-7
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    What formula is best for milk protein allergy

    Pediatr Gastroenterol Hepatol Nutr. 2014 Mar17(1):1-5. doi: 10.5223/pghn.2014.17.1.1. Epub 2014 Mar 31.

  • von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grübl A, Wichmann HE, Bauer CP, Reinhardt D, Berdel D; German Baby Nutritional Intervention Study Group. Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Baby Nutritional Intervention Study. J Allergy Clin Immunol. 2007;119:718-25
  • Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW.

    Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391-7.

  • Moissidis I, Chaidaroon D, Vichyanond P, Bahna SL. Milk-induced pulmonary disease in infants (Heiner syndrome). Pediatr Allergy Immunol 2005;16:545-52
  • Leonard SA, Nowak-Wegrzyn AH; Baked Milk and Egg Diets for Milk and Egg Allergy Management. Immunol Allergy Clin North Am. 2016 Feb36(1):147-59. doi: 10.1016/j.iac.2015.08.013.

  • Levy Y, Segal N, Garty B, Danon YL.

    Lessons from the clinical course of IgE-mediated cow milk allergy in Israel. Pediatr Allergy Immunol 2007: 18: 589-93

  • A formal challenge with cow's milk remains the best diagnostic test.
  • 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. 2015 Apr 14113(7):1102-12. doi: 10.1017/S000711451500015X. Epub 2015 Mar 17.

  • Boyle RJ, Ierodiakonou D, Khan T, et al; Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ. 2016 Mar 8352:i974. doi: 10.1136/bmj.i974.

  • Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M.

    The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011;127:647-53

  • PUFAs, nucleotides, glycoproteins, oligosaccharides and microRNA, capable in turn to exert immune functions.

  • In settings where oral food challenge is not considered a requirement for making a diagnosis of IgE-mediated cow's milk allergy, a positive SPT and/or ImmunoCAP (cut-off: 0.35 kUI/L) can be used and diagnostic tests in case of high pre-test probability.
  • Fiocchi A, Bouygue GR, Albarini M, Restani P.

    Molecular diagnosis of cow's milk allergy. Curr Opin Allergy Clin Immunol. 2011;11:216-21

  • Vanto T, Helppila S, Juntunen-Backman K, et al. Prediction of the development of tolerance to milk in children with cow milk hypersensitivity. J Pediatr 2004:144: 218-22.
  • Miceli Sopo S et al. The predictive worth of specific immunoglobulin E levels for the first diagnosis of cow's milk allergy.

    What formula is best for milk protein allergy

    A critical analysis of pediatric literature. Pediatr Allergy Immunol 2007; 18:575-82

  • Better immunologic system development & immune responses

  • Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast -fed infants. J Pediatr 1982;101:906-10
  • Novembre E, Vierucci A. Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy 2001;56 Suppl 67:105-8.
  • Agostoni C, Terracciano L, Varin E, et al; The Nutritional Worth of Protein-hydrolyzed Formulae. Crit Rev Food Sci Nutr. 201656(1):65-9. doi: 10.1080/10408398.2012.713047.

  • Martelli A, De Chiara A, Corvo M, Restani P, Fiocchi A.

    Beef allergy in children with cow's milk allergy. Cow's milk allergy in children with beef allergy. Ann Allergy, Asthma Immunol 2002;89: S38-43

  • Iacono G, Carroccio A, Cavataio F, Montalto G, Soresi M, Balsamo V. Use of ass's milk in multiple food allergy. J Pediatr Gastroenterol Nutr 1992, 14:177-181
  • Powell GK. Milk-and soy-induced enterocolitis of infancy. J Pediatr 1978;93:553-60
  • maternal antibodies, including anti-idiotypic antibodies, capable to sustain and regulate immune cell populations through a priming of fetal and neonatal cells;

  • 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. 2015 Jun 341:42. doi: 10.1186/s13052-015-0141-7.

  • Fiocchi A, Terracciano L, Bouygue GR, Veglia F, Sarratud T, Martelli A, Restani P. Incremental prognostic factors associated with cow's milk allergy outcomes in baby and kid referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol. 2008;101:166-73
  • The Milk Ladder; MAP Guideline

  • In such settings, a negative SPT and/or ImmunoCAP with whole milk (cut-off: 0.35 kUI/L) can be used as rule-out tests in case of low pre-test probability.
  • Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA.

    Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol 2004;113:558-60.

  • Fiocchi A, Restani P, Leo G, Martelli A, Bouygue GR, Terracciano L, Ballabio C, Valsasina R. Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics. 2003; 112:359-6
  • Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome. J Pediatr 1990; 116:862-7.
  • cytokines (TGF-β2, IL-10, thymic stromal lymphopoietin) and chemokines, influencing the development of allergy and atopic diseases;

  • Hill DJ, Firer MA, Ball G, Hosking CS.

    Natural history of cow's milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy 1993; 23: 124-31.

  • Simons FE, Ardusso LR, Bilò MB, El-Gamal YM, Ledford DK, Ring J, Sanchez-Borges M, Senna ge, Sheikh A, Thong B for the World Allergy Organization. World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis. World Allergy Organization Journal 2011; 4: 13-37
  • García-Ara MC, Boyano-Martínez MT, Díaz-Pena JM, Martín-Muñoz MF, Martín-Esteban M.

    Cow's milk-specific immunoglobulin E levels as predictors of clinical reactivity in the follow-up of the cow's milk allergy infants. Clin Exp Allergy. 2004;34:866-70;

  • Werfel SJ, Cooke SK, Sampson HA. Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol 1997; 99:293-300
  • Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS; Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology. Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009;123(6 Suppl):S365-83
  • 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. 2009 Apr123(4):883-8. doi: 10.1016/j.jaci.2008.12.1125. Epub 2009 Feb 20.

  • Fewer infections, of shorter duration.

  • Nowak-Wegrzyn A et al. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol 2008, 122:342-7
  • Fiocchi A, Brozek J, Schunemann HJ, Bahna SL, von Berg A, Beyer K, et al. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines.

    WAO Journal 2010; 3:57-61

  • In any case of high uncertainty, challenges remain necessary.
  • Fiocchi A, Restani P, Riva E, Mirri GP, Santini I, Bernardo L, Galli CL. Heat treatment modifies the allergenicity of beef and bovine serum albumin. Allergy, 1998; 53:798-802
  • hormones and growth factors, influencing the maturation of the baby gut and of the associated lymphoid tissues;

  • Iodine deficiency during pregnancy is associated with negative cognitive outcomes [19, 20].

  • Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U. Standardization of food challenges in patients with immediate reactions to foods-position paper from the European Academy of Allergology and Clinical Immunology.

    Allergy 2004;59:690-7

  • Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998: 101: e8.
  • Bahna SL. Blind food challenge testing with wide-open eyes. Ann Allergy 1994, 72: 235-8.
  • Skripak JM et al. Mammalian milk allergy: avoidance strategies and oral desensitization. Curr Opin Allergy Clin Immunol. 2009;9:259-64
  • Muraro A, Roberts G, Clark A, Eigenmann PA, Halken S, Lack G, Moneret-Vautrin A, Niggemann B, Rancé F. The management of anaphylaxis in childhood: position paper of the European Academy of allergy and clinical immunology.

    Allergy 2007; 62:857-71

  • 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. 2017 Aug 237:26. doi: 10.1186/s13601-017-0162-y. eCollection 2017.

  • Mehl A., Rolinck-Werninghaus C., Staden U., Verstege A., Wahn U., Beyer K., Niggemann B. The atopy patch test in the diagnostic workup of suspected food-related symptoms in children J Allergy ClinImmunol 2006;118:923-9
  • Celik-Bilgili S, Mehl A, Verstege A et al. The predictive worth of specific immunoglobulin E levels in serum for the outcome of oral food challenges, Clin Exp Allergy 2005;35:26-73
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    Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy 1999; 29: 91-6.

  • Cows milk protein allergy in children; NICE CKS, June 2015 (UK access only)

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  • Terracciano L, Bouygue G, Sarratud T, Veglia F, Martelli A, Fiocchi A. Impact of dietary regimen on the duration of cow's milk allergy.

    a random allocation study. Clin Exp Allergy 2010; 40:637-42

  • American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic baby formulas. Pediatrics 2000;106:346-9.
  • Better brain development

  • Perry TT, Matsui EC, Kay Conover-Walker M. Wood RA. The relationships of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol 2004;114:144-9

Faced with an baby with CMA, the pediatrician must dictate an avoidance regimen. This will include a substitute; the best is – of course – breastfeeding with a mother’s diet free of milk products [1].

Breastfeeding is strongly recommended as the preferred way of baby feeding [14]. Compared to formula-fed infants, the breastfed show:

  1. Different nutritional status

  2. Different gut microflora

  3. Different growth patterns

  4. Better brain development

  5. Better immunologic system development & immune responses

  6. Fewer infections, of shorter duration.

Despite the fact that formulae are modeled after breastmilk, the human milk composition maintains its unique characteristics. It contains a series of inimitable molecules with potential immune modulating activities.

Examples comprise:

  1. cytokines (TGF-β2, IL-10, thymic stromal lymphopoietin) and chemokines, influencing the development of allergy and atopic diseases;

  2. hormones and growth factors, influencing the maturation of the baby gut and of the associated lymphoid tissues;

  3. maternal antibodies, including anti-idiotypic antibodies, capable to sustain and regulate immune cell populations through a priming of fetal and neonatal cells;

  4. PUFAs, nucleotides, glycoproteins, oligosaccharides and microRNA, capable in turn to exert immune functions.

Probably also for these reasons breastfeeding has been shown to influence a series of outcomes, including the establishment of gut microbiota, the prevention of overweight and obesity, the development of immunoallergic parameters and the neural development.

This final aspect is being actively investigated, and in the final few years offers us some new acquisitions that can be of interest in the general management of CMA.

Breastfed babies display significant structural differences in the brain anatomy compared with those that received baby formula: for instance, they present a longer corpus callosum, a higher ganglyothalamic ovoid diameter [15], a higher cortical thickness in parietal lobules [16]. Probably related to these effects, breastfeeding positively influences cognitive development and general intelligence [14].

From studies in cohorts of non-allergic infants it is known that the neural programming displays some ‘windows of plasticity’, during which environmental, nutritional, and microbiological factors may influence the brain function, generating diverse behavioral competence trajectories [17].

Numerous animal studies own focused on the effects of nutrition on brain development demonstrating that changes in dietary nutrients can alter brain morphology as well as its biochemical functions. Before the year 2010, however, much of the evidence from human studies was retrospective. Then epidemiological birth cohort studies indicated that folate, n-3 fatty acids, iodine and iron istered in pregnancy may influence the brain development in healthy children [18].

In specific, from the ALSPAC cohort we know that:

  1. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor skills, communication, and social development scores. For each outcome measured, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome [19]

  2. Maternal seafood intake during pregnancy of less than 340 g per week is associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ), compared with mothers who consumed more than 340 g per week [19]

  3. Iodine deficiency during pregnancy is associated with negative cognitive outcomes [19, 20].

After birth, the more implicated nutrients in the global development of infants are protein supply, PUFAs, Vitamins B12, C, A and D, iron, iodine, choline, zinc, selenium, and copper.

Independently or in combination, their nutritional availability may influence cognitive performance behavior [21].

What formula is best for milk protein allergy

Other studies failed to identify positive effects of breastfeeding on early life intelligence and cognitive growth from toddlerhood through adolescence [22], while an improved performance in intelligence of breastfed children was found at age 30 [23]. Taken together, the recent human studies indicate that the association among breastfeeding and improved performance in intelligence tests is not casual [24].

As a case in point, essential fatty acids frolic a central role in brain development of infants: humans can synthesize saturated and monounsaturated fatty acids but cannot synthesize the n-3 and the n-6 families of PUFA. The parent fatty acids of these families, alpha linolenic acid (18 carbons, three double bonds with the first double bond in the n-3 position, C18:3n-3, ALA) and linoleic acid (C18:2n-6, LA) are essential fatty acids and must be present in the diet.

ALA is converted to eicosapentaenoic acid (C20:5 n-3, EPA) then to docosahexaenoic acid (C22:6n-3, DHA), while LA is converted to arachidonic acid (C20:4n-6, AA). DHA is a critical component of cell membranes, especially in the brain and retina. AA is both a membrane component and a precursor to potent signaling molecules, the prostaglandins and leukotrienes. The human milk always contains both AA and DHA, while in the past baby formulae had neither. Interventional studies failed to discover evidence that prenatal fish-oil (and folic acid) supplementation may influence the cognitive development of children at 6.5 y of age, but a high DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring [25].

Also, associations of maternal LC-PUFA status with kid emotional and behavioral problems were found in an epidemiologic study [26]. Nowadays, special formulae for the treatment of CMA are not in line with these characteristics of HM (Table 1).

Another significant component of breast milk is folic acid; its appropriate availability at the onset of pregnancy is associated with brain volume (Fig. 1). In children with low maternal folate levels, the head grows 0.1 mm per week less than in the controls [27]. This may translate in 1.9 million neurons and 1.9 billion synapses less per week.

Low maternal folate status during early pregnancy was also found associated with a higher risk of emotional and behavioral problems in the offspring [28]. The use of prenatal folic acid supplements around the time of conception has been associated with a lower risk of autistic disorder [29]. Human milk provides sufficient folate intake, essential for normal growth and brain development; heat treatment in the breastmilk banks may critically reduce its quantity [30].

Breastfeeding also influences the gut microbiota. Its establishment soon after birth is conditioned by factors as the type of delivery (passage through the birth canal vs.

caesarean section), socioeconomic and climatic environment (born in developed vs. developing countries), and immune system development during pregnancy, antibiotic treatments, and contacts with parents, siblings and hospital staff [31]. Dietary factors (breast vs. formula feeding) are of prominent importance in this context.

The gut microbiota as a major topic of research interest in biology has increased in recent years . Studies are assessing the influence of variations in the composition of the gut microbiota on diseases, ranging from inflammation to obesity.

Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behavior. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs propose a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain [32]. It is now generally accepted that a stable gut microbiota is essential for normal gut physiology and contributes to appropriate signaling along the gut–brain axis and, thereby, to the healthy status of the individual, as shown on the left-hand side of Fig.

2. The right-hand side of the figure indicates how intestinal dysbiosis can adversely influence gut physiology, leading to inappropriate gut–brain axis signaling and associated consequences for CNS functions and resulting in disease states. Conversely, stress at the level of the CNS can affect gut function and lead to perturbations of the microbiota [33]. Thus, the emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complicated CNS disorders.

Of course, every these activities of breastfeeding are mediated through epigenetic activities of the diet, especially during prenatal and early postnatal life.

Diets high in choline, methionine, folate, vitamin B6 and vitamin B12 increase DNA and histone methylation altering gene expression and generating permanent changes in development [34]. Early-life nutritional exposures, therefore, can act on the development of asthma, allergy, and obesity through epigenetic mechanisms [35].

Cow’s Milk Allergy in Children

Editor's Note: The "Cow's Milk Allergy in Children" manuscript was submitted by the tardy Cassim Motala, MD and kindly updated and completed on his behalf by Alessandro Fiocchi, MD.

Professor Motala was a member of the WAO Web Editorial Board and contributed his time and knowledge of pediatric allergy to numerous of WAO's initiatives.

Posted: October 2011
Updated: July 2012

Cassim Motala, MD
School of Kid & Adolescent Health
University of Cape Town and Red Cross War Memorial Children's Hospital
Capetown, South Africa
Alessandro Fiocchi, MD
Paediatric Division
Department of Kid and Maternal Medicine
University of Milan Medical School at the Melloni Hospital
Milan, Italy

Treatment of Cow's Milk Allergy in Children

Specific oral tolerance induction

Avoidance is hard as cow's milk protein is ubiquitous and accidental allergic reactions in children with CMA are common.nowak, 22 Specific oral tolerance induction (SOTI) or desensitization is a promising therapy for IgE-mediated.39 Randomized controlled trials own reported that about 35% of children become fully tolerant to cow's milk protein after SOTI; 15-20% may not finish the procedure because of severe adverse reactions; no fatal events own been documented.

Follow-up data on children who became tolerant to cow's milk protein is inadequate and it is unclear where tolerance is transient on permanent.40 Patients undergoing SOTI require careful monitoring. Various protocols own been described, some audacious and some prudent and the procedure is extremely time consuming. For these reasons, SOTI should be regarded for now as experimental therapy and must only be undertaken by practitioners who own been trained in this procedure.1

Conclusions

Cow's milk allergy is one of the most frequent manifestations of food allergy and may present as an IgE- or non-IgE-mediated disease.

Patients with IgE-mediated CMA and asthma are at risk of potentially severe allergic reactions (anaphylaxis). The diagnosis of CMA relies primarily on clinical evaluation supported by skin prick testing and in vitro measurement of specific IgE. CMA can be adequately treated with dietary manipulation including avoidance cow's milk protein products. Every cases of CMA must be managed in collaboration with an experienced dietician who has expertise in food allergy.

What formula is best for milk protein allergy

The dietician's role is to provide advice/recipes/education (reading food labels, checking for hidden ingredients, etc.) and to ensure nutritional adequacy. The condition can be handled at the primary level, but whenever possible it should be referred to a specialist with expertise in allergy. This becomes mandatory in severe cases of cow's milk allergy.

Diagnosis

Immediate reactions

These happen <2 hours after ingestion. The most frequent manifestations are IgE-mediated cutaneous (urticaria, angioedema, acute flare-up of atopic eczema) and gastrointestinal (vomiting, diarrhea, colic) reactions.

Cow's milk protein-induced enterocolitis syndrome is an immediate-onset, non-IgE-mediated, condition. It is characterized by initial symptoms occurring during the first months of life as repeated vomiting episodes sometimes leading to dehydration. Symptoms might be extremely severe and mimic sepsis. A characteristic feature of this syndrome is a symptom free interval of up to several hours between ingestion of milk, most often a cow's milk protein-based formula, and the first symptoms.4 Respiratory manifestations (asthma, allergic rhinitis) are infrequent, especially as isolated symptoms. There is a belief among some members of the lay public that the consumption of milk and dairy products increases the production of mucus in the respiratory tract – there is no scientific confirmation of this.5 Anaphylaxis is the most severe manifestation.

Currently defined as "a severe systemic or generalised severe allergic reaction",6 this potentially life-threatening condition greatly adds to the burden of living with milk allergy. Diagnostic criteria include sudden onset involving skin, mucosa, or both, with at least one respiratory symptom such as dyspnoea, bronchospasm, stridor, PEF reduction, hypoxemia, drop in blood pressure, organ dysfunction symptoms (hypotonia, syncope, etc), gastrointestinal symptoms (colic, vomiting) and shock.7 This happens almost immediately (within minutes and up to two hours) after the ingestion of cow's milk or dairy products and is clinically similar to anaphylaxis from foods diverse from CM.8

Milk substitutes not recommended for treatment of CMA

Partially-hydrolyzed formulae (pHF) are contra-indicated in the treatment of CMA because of the high content of residual allergen (only 12-26% of cow's milk protein is hydrolyzed in the currently available pHFs) and a definite risk of allergic reactions to these products.

By definition, they do not meet the AAP standards for hypoallergenicity. Goat, sheep, buffalo, horse milk, and whole rice milk are also not recommended — these milks are not nutritionally adequate and often cross-react with proteins in cow's milk.

Alternate formula (milk substitutes)
See Table 1

The recently published international guidelines1, kemp recommend extensively hydrolyzed formulae (eHF) or amino-acid based formulae (AAF) as first line alternatives for children with CMA.

In general, eHFs are nutritionally adequate and well-tolerated by children allergic to cow's milk and other foods but their main drawbacks are their bitter taste, expense (2-3 times the cost of standard formula), and their potential to cause anaphylaxis. As such formula are obtained from casein or whey proteins, residual antigenic activity has been found in every types of extensive hydrolysates by both in vitro and in vivo studies, which show that any formula may potentially trigger reactions in infants allergic to cow's milk.35 Current guidelines define a therapeutic formula as one that is tolerated by at least 90% (with 95% confidence) of CMPA infants.36 The antigenicity and allergenicity of hydrolysate formulae is partially dependent on their molecular weight, even if prevention studies protest that formulae with a higher mean molecular weight may be associated with a better outcome in prevention of CMA,37 and the definition of hypoallergenic formula does not rely on the molecular weight.

Rice-hydrolized formula (RHF) are considered a second-line resource due to their not universal availability.1 Where available, RHF can be considered instead of eHF. AAFs are safe and palatable but are exorbitantly expensive (6-8 times the cost of eHFs) and not widely available. Reimbursement for AAFs by health funders is also a potential problem as they are not generally considered as therapeutic agents. Soy formula is well tolerated in up to 85% of infants with IgE-mediated CMA but only in 50% of those with non-IgE mediated CMA.

However, soya is not recommended in infants under 6 months because of concerns about possible hormonal effects on the reproductive system (shown in animal studies)- presumed due to phyto-oestrogens in the form of isoflavones (genistein,diadzen and their glycosides) present in soya protein. To date, no studies own evaluated safety of soya formula in humans-such studies are much needed.

Table 1. Choosing the appropriate substitute formula in diverse presentations1

Clinical presentation 1st choice 2nd choice 3rd choice
Anaphylaxis AAF+ eHF SF
Immediate gastrointestinal allergy eHF§♭ AAF^/SF°
Food protein-induced enterocolitis syndrome (FPIES) AAF eHF*
Asthma and rhinitis eHF§♭ AAF^/SF°
Acute urticaria or angioedema eHF§♭ AAF^/SF°
Atopic dermatitis eHF§♭ AAF^/SF°
Gastroesophageal reflux disease (GERD) eHF AAF
Allergic eosinophilic oesophagitis AAF
Cow's milk protein-induced enteropathy eHF§♭ AAF
Constipation eHF AAF Donkey milk
Severe irritability (colic) eHF AAF
CM protein-induced gastroenteritis and proctocolitis eHF AAF
Milk-induced chronic pulmonary disease (Heiner's syndrome) ** AAF^ SF eHF

+ recommendation 7.1
recommendation 7.2
* if AAF refusal
§ subject to local availability, HRF can be considered instead than eHF (7.4)
# subject to a negative SPT with the specific formula (panel recommendation)
^ AAF if a relatively high worth on avoiding sensitization by SF and/or a low worth on resource expenditure are placed.
° SF if a relatively low worth on avoiding sensitization by SF and/or a high worth on resource expenditure are placed.
** this suggestion attributes a high worth on avoiding exposure to even residual antigenic cow's milk proteins.
based on reports from one case series38
+given that more than 50% of such children are allergic to soy, a careful clinical evaluation is necessary (panel recommendation)1

Avoidance of cow's milk protein

Patients with cow's milk allergy must strictly avoid cow's milk and cow's milk protein-based products.

Patients and their families must be instructed to read labels and identify milk-containing products. Particularly in young children, a well-balanced diet with sufficient intake of calcium and other essential nutriments must be warranted. The input of a paediatric dietician is most helpful in these patients. Mothers of breast-fed infants with CMA should continue breast-feeding but avoid causal foods. Recent studies lift the question of the possibility of following an incomplete milk avoidance in less severe cases of CMA. Children receiving limited, extensively heated milk reported no acute milk-induced allergic reactions as a result of this diet, suggesting that a change from a milk avoidance diet to a milk-limited diet could provide a substantial improvement to the quality of life of milk-allergic individuals.26, 27 Moreover, baked milk tolerant consuming baked products own been recently indicated more likely to own unheated milk tolerance than subjects not consuming such products.28 This is in conflict with the observation that CMA children exposed to little doses of milk proteins in eHF may display a longer duration of CMA.29 Thus, exposing such children to milk allergens remains an unwarranted practice.

The literature does not report a single case of an adverse reaction to lactose ingestion among children with CMA, and a prospective study of the allergenicity of whey-derived lactose investigated by serology and DBPCFC did not document such reactions.30 Thus, even if lactose ingestion may per se carry risks of cow's milk protein contamination (as seen from incidents after inhalation of lactose-containing drugs31) the entire elimination of lactose from the diet of children with CMA is not warranted.

Conversely, beef allergy is possible in children with CMA.32 While almost every children allergic to beef are also allergic to milk,33 industrial treatment, more than home cooking, may modify the allergic reactivity of this meat in beef-sensitive children,34 thus making industrially freeze-dried or homogenized beef safe alternatives to butcher's meat cooked at home.

Again thus, although beef allergy should be considered, entire avoidance of beef by every children allergic to cow's milk is not justified.

Clinical evaluation

A comprehensive history (including a family history of atopy) and careful physical examination form the foundation for the diagnosis and management of CMA. Unfortunately, there is not one symptom that is pathognomonic for cow's milk allergy, but the timing and pattern of symptoms aid the diagnosis. For instance, in a patient that presents an acute anaphylaxis after ingestion of milk without another food or trigger, there is a extremely strong clinical suspicion.

Symptoms of CMA happen often, but not always, within the first weeks after the introduction of cow's milk proteins. Numerous of the children with cow's milk allergy develop symptoms in at least two of the following organ systems: gastrointestinal (50-60%), skin (40-50%) and respiratory tract. Temporal relationship between milk ingestion and onset of symptoms should also be assessed to distinguish immediate from non-IgE-mediated reactions.

Diagnostic tests

IgE-mediated CMA. Skin-prick testing (SPT) with unused milk or commercial reagents and ImmunoCAP-RAST (for determining specific IgE against cow's milk proteins as caseins, lactoglobulin, and alpha-lactalbumin), are the currently available tests.

The performance characteristics of these tests own been described in diverse settings. In children older than two years, an SPT reaction with a wheal diameter ≥8mm14 or milk specific IgE level ≥15,0 ku/L, the likelihood is 95% that the kid will own a positive milk challenge. The corresponding wheal size in children younger than two years is 6mm diameter5 and milk-specific IgE ≥5,0ku/L16 respectively. Studies on specific caseloads are limited by several factors inherent to the characteristics of the studied group, such as clinical conditions (AD, asthma, GI), their severity, the percentage of polyallergic patients, and age and geographical differences.17 Thus, the use of sensitization tests is dependent on the clinical setting and on the pre-test probability of disease.

For this reason, the whole matter has been subjected to systematic review and metanalysis in the preparation of the Diagnosis and Rationale Against Cow's Milk Allergy (DRACMA) guidelines. Including studies published up to September 2009, the DRACMA panel reviewed the evidence summaries and the draft guidelines, and made recommendations on diagnosis.

According to these recommendations,

  1. Hill DJ, Firer MA, Ball G, Hosking CS. Natural history of cow's milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy 1993; 23: 124-31.
  2. Skripak JM, Matsui EC, Mudd K, Wood RA.

    The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120:1172-7

  3. Bahna SL. Blind food challenge testing with wide-open eyes. Ann Allergy 1994, 72: 235-8.
  4. Moissidis I, Chaidaroon D, Vichyanond P, Bahna SL. Milk-induced pulmonary disease in infants (Heiner syndrome). Pediatr Allergy Immunol 2005;16:545-52
  5. Muraro A, Roberts G, Clark A, Eigenmann PA, Halken S, Lack G, Moneret-Vautrin A, Niggemann B, Rancé F. The management of anaphylaxis in childhood: position paper of the European Academy of allergy and clinical immunology. Allergy 2007; 62:857-71
  6. Hill DJ, Heine RG, Hosking CS, Brown J, Thiele L, Allen KJ, Su J, Varigos G, Carlin JB.IgE food sensitization in infants with eczema attending a dermatology department.J Pediatr 2007;151:359-63.
  7. Simons FE, Ardusso LR, Bilò MB, El-Gamal YM, Ledford DK, Ring J, Sanchez-Borges M, Senna ge, Sheikh A, Thong B for the World Allergy Organization.

    World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis. World Allergy Organization Journal 2011; 4: 13-37

  8. Terracciano L, Bouygue G, Sarratud T, Veglia F, Martelli A, Fiocchi A. Impact of dietary regimen on the duration of cow's milk allergy. a random allocation study. Clin Exp Allergy 2010; 40:637-42
  9. Mehl A., Rolinck-Werninghaus C., Staden U., Verstege A., Wahn U., Beyer K., Niggemann B. The atopy patch test in the diagnostic workup of suspected food-related symptoms in children J Allergy ClinImmunol 2006;118:923-9
  10. Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA.

    Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol 2004;113:558-60.

  11. Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome. J Pediatr 1990; 116:862-7.
  12. Fiocchi A, Restani P, Riva E, Mirri GP, Santini I, Bernardo L, Galli CL. Heat treatment modifies the allergenicity of beef and bovine serum albumin. Allergy, 1998; 53:798-802
  13. Høst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K.

    Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood. Pediatr. Allergy Immunol. 2002;3:23-28;

  14. Savilahti E. Food-induced malabsorption syndromes. J Pediatr Gastroenterol Nutr 2000; 30 Suppl: S61-S66
  15. Werfel SJ, Cooke SK, Sampson HA. Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol 1997; 99:293-300
  16. Caminiti L, Passalacqua G, Barberi S, Vita D, Barberio G et al.

    A new protocol for specific oral induction in children with IgE-mediated cow's milk allergy. Allergy Asthma Proc 2008;30:443-8

  17. It should be performed with physician supervision regardless of food-specific IgE value.
  18. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW.

    Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391-7.

  19. In such settings, a negative SPT and/or ImmunoCAP with whole milk (cut-off: 0.35 kUI/L) can be used as rule-out tests in case of low pre-test probability.
  20. In settings where oral food challenge is not considered a requirement for making a diagnosis of IgE-mediated cow's milk allergy, a positive SPT and/or ImmunoCAP (cut-off: 0.35 kUI/L) can be used and diagnostic tests in case of high pre-test probability.
  21. Nowak-Wegrzyn A et al.

    Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol 2008, 122:342-7

  22. If challenge is positive, out of a research setting sensitization tests may not be necessary.
  23. Powell GK. Milk-and soy-induced enterocolitis of infancy. J Pediatr 1978;93:553-60
  24. In any case of high uncertainty, challenges remain necessary.
  25. Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast -fed infants. J Pediatr 1982;101:906-10
  26. Järvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ Sampson HA.

    B-cell epitopes as a screening instrument for persistent cow's milk allergy, J. Allergy Clin Immunol 2002;110:293-7

  27. Longo G, Barbi E, Berti I, et al. Specific oral tolerance induction in children with extremely severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008;121:343-347.
  28. Miceli Sopo S et al. The predictive worth of specific immunoglobulin E levels for the first diagnosis of cow's milk allergy. A critical analysis of pediatric literature. Pediatr Allergy Immunol 2007; 18:575-82
  29. Novembre E, Vierucci A. Milk allergy/intolerance and atopic dermatitis in infancy and childhood.

    Allergy 2001;56 Suppl 67:105-8.

  30. Vanto T, Helppila S, Juntunen-Backman K, et al. Prediction of the development of tolerance to milk in children with cow milk hypersensitivity. J Pediatr 2004:144: 218-22.
  31. Kim JS et al. Dietary baked milk accelerates the resolution of cow's milk allergy in children. J Allergy Clin Immunol. 2011;128:125-131
  32. Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS; Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology. Work Group report: oral food challenge testing. J Allergy Clin Immunol.

    2009;123(6 Suppl):S365-83

  33. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998: 101: e8.
  34. Celik-Bilgili S, Mehl A, Verstege A et al. The predictive worth of specific immunoglobulin E levels in serum for the outcome of oral food challenges, Clin Exp Allergy 2005;35:26-73
  35. Iacono G, Carroccio A, Cavataio F, Montalto G, Soresi M, Balsamo V. Use of ass's milk in multiple food allergy. J Pediatr Gastroenterol Nutr 1992, 14:177-181
  36. Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M.

    The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011;127:647-53

  37. A formal challenge with cow's milk remains the best diagnostic test.
  38. Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: Efficacy and clinical patterns of reaction.

    Allergy. 2007;62:1261-1269.

  39. Fiocchi A, Bouygue GR, Albarini M, Restani P. Molecular diagnosis of cow's milk allergy. Curr Opin Allergy Clin Immunol. 2011;11:216-21
  40. Fiocchi A, Restani P, Leo G, Martelli A, Bouygue GR, Terracciano L, Ballabio C, Valsasina R. Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics. 2003; 112:359-6
  41. von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grübl A, Wichmann HE, Bauer CP, Reinhardt D, Berdel D; German Baby Nutritional Intervention Study Group.

    Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Baby Nutritional Intervention Study. J Allergy Clin Immunol. 2007;119:718-25

  42. Terracciano L, Isoardi P, Arrigoni S, Zoja A, Martelli A. Milk, Soy and Rice Hydrolysates. Ann Allergy, Asthma & Immunology 2002;89: 86-90
  43. Martelli A, De Chiara A, Corvo M, Restani P, Fiocchi A. Beef allergy in children with cow's milk allergy. Cow's milk allergy in children with beef allergy. Ann Allergy, Asthma Immunol 2002;89: S38-43
  44. Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children.

    Clin Exp Allergy 2000;30:1540-6

  45. American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic baby formulas. Pediatrics 2000;106:346-9.
  46. Skripak JM et al. Mammalian milk allergy: avoidance strategies and oral desensitization. Curr Opin Allergy Clin Immunol. 2009;9:259-64
  47. Fiocchi A, Brozek J, Schunemann HJ, Bahna SL, von Berg A, Beyer K, et al. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. WAO Journal 2010; 3:57-61
  48. Fiocchi A, Terracciano L, Bouygue GR, Veglia F, Sarratud T, Martelli A, Restani P.

    Incremental prognostic factors associated with cow's milk allergy outcomes in baby and kid referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol. 2008;101:166-73

  49. García-Ara MC, Boyano-Martínez MT, Díaz-Pena JM, Martín-Muñoz MF, Martín-Esteban M. Cow's milk-specific immunoglobulin E levels as predictors of clinical reactivity in the follow-up of the cow's milk allergy infants. Clin Exp Allergy. 2004;34:866-70;
  50. Niggemann B, Sielaff B, Beyer K, Binder C, Wahn U. Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy 1999; 29: 91-6.
  51. Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, et al.

    Specific IgE levels in the diagnosis of immediate hypersensitivity to cow's milk protein in the baby. J Allergy Clin Immunol 2001: 107: 185-90

  52. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001: 107: 891-6
  53. Levy Y, Segal N, Garty B, Danon YL. Lessons from the clinical course of IgE-mediated cow milk allergy in Israel. Pediatr Allergy Immunol 2007: 18: 589-93
  54. Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U. Standardization of food challenges in patients with immediate reactions to foods-position paper from the European Academy of Allergology and Clinical Immunology.

    Allergy 2004;59:690-7

  55. Perry TT, Matsui EC, Kay Conover-Walker M. Wood RA. The relationships of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol 2004;114:144-9

The prognostic and diagnostic utility of using specific proteins at ImmunoCAP or microarrayed platforms remains to be established.18

Non-IgE-mediated CMA: There are no dependable tests for the diagnosis of non-IgE mediated CMA. Initial diagnosis is based on a suggestive history and absence of positive SPT or ImmunoCAP-RAST.

In these patients, the diagnosis primarily relies on a successful milk avoidance diet with clinical relapses after re-exposure to cow's milk proteins. In patients with atopic dermatitis and eosinophil esophagitis in whom non-IgE mediated cow's milk allergy is suspected, Atopy Patch testing (APT) may be a helpful diagnostic tool.19

Elimination-challenge testing: Food challenges remain the definitive procedure for the diagnosis of CMA.

If the symptoms substantially improve or vanish after 2-4 weeks on an elimination diet, an open challenge with a formula based on whole cow's milk protein should be performed. Clinicians should be aware that the severity of a past reaction might not predict the severity of a challenge reaction, particularly after a period of dietary exclusion. Previous mild reactions may be followed by anaphylactic reactions in some infants with CMA. For this reason, open challenges should ideally be performed in a setting where resuscitation facilities are available. In a case of cow's milk-induced anaphylaxis, a challenge is contraindicated unless SPTs and/or specific IgE measurements show improvement.

In these cases, the challenge should always be performed in a hospital setting.

Positive challenge: CMA confirmed

If symptoms of CMA re-appear, the suspected diagnosis of CMA is confirmed and the baby should be maintained on an elimination diet using a milk substitute (discussed below) for at least 6 months. The challenge is then repeated. If it is possible to follow the baby with IgE-mediated allergy with SPTs and/ or specific IgE determination, improvement of these tests would assist in choosing the time point of challenge.

Supplementary feeding should be introduced carefully to avoid accidental intake of cow's milk protein. Protocols of milk challenges own been published in diverse guidelines.1, 20, 21 Of importance, every guidelines emphasize the rules for milk challenge in immediate CMA, while the interpretation of delayed reactions occurring up to 7,22 9,23 or 14 days24 is more controversial. The diagnosis of delayed reaction may be hard because when the kid returns home, multiple environmental factors (infections, dietary factors, emotional, casual contacts, sports-related physical activity) may impinge diagnostic interpretation.

Frequently, immediate and delayed symptoms are present concomitantly in the same child.25

Negative challenge: No CMA

Children who do not develop symptoms on the cow's milk formula during challenge and up to one week after follow-up can resume their normal diet, although they should still be carefully monitored. Clinicians should advise parents to be attentive for delayed reactions, which may evolve over several days following the challenge.

Pathogenesis

CMA results from an immunological reaction to one or more milk proteins. This immunological basis distinguishes CMA from other adverse reactions to cow's milk protein such as lactose intolerance.

CMA may be immunoglobulin E (IgE) or non-IgE-mediated and may be a manifestation of the atopic diatheses and multiple food allergies. Reactions to other foods (depending on the regional dietary intake) may happen in combination with CMA. Non-IgE-mediated disorders generally involve T-Cells (or eosinophils), present mainly with gastrointestinal symptoms and are less likely to develop multiple food allergies. IgE- and non-IgE-mediated mechanisms may frolic a role in the pathogenesis of atopic dermatitis and the eosinophilic gastrointestinal disorders (EGIDs).

Introduction

The estimated prevalence of cow's milk allergy (CMA) varies between 0.25% and 4.9%, being higher in children than adults.1 The prevalence is higher in referral populations, depending on the nature of the basic condition.

For instance, in a consecutive series with moderate atopic eczema referred to a University-affiliated dermatology department, SPT showed 16% of infants with IgE against CMP.2 In a group of infants and children with AD and no other allergic manifestations, 37% had a diagnosis of CMA.3 Cow's milk allergy can develop in exclusively or partially breast-fed infants, when cow's milk protein is introduced into the feeding regime.

The incidence of CMA is lower in exclusively breast-fed infants compared to formula-fed or mixed-fed infants, and clinical reactions in the breast-fed group are mostly mild to moderate. This might be related to lower levels of CMP in breast milk compared to cow's milk. Immunomodulators in breast milk and differences in gut flora between breast-fed and formula-fed infants may also frolic a role.

Clinical Manifestations

The clinical manifestations of CMA depend to a grand extent on the type of immunological reaction involved.

Delayed reactions

These immunological, non-IgE-mediated reactions happen several hours or days after milk consumption.

Atopic dermatitis is observed in approximately 10-15% of young children. It is primarily because of the dryness of skin and is linked to hereditary factors; however, approximately one third of patients with moderate to severe atopic dermatitis present with flares of eczema linked to a food allergy.9 Cow's milk, hen's egg, and peanuts are the foods most frequently involved. GI disorders include food protein-induced (FPI) enterocolitis, enteropathy and proctolitis.10 Milk induced proctocolitis is mostly observed in young infants while exclusively breast-fed.11 FPI disorders are typically cow's milk and soya protein induced, but they may also happen with ingestion of solid foods including, fish, chicken, turkey, corn and vegetables.

FPI-enterpathy generally presents with diarrhea, mild to moderate steatorrhea (80% of cases) and poor weight acquire. The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.12 Rectal bleeding is the usual presenting feature of FPI-colitis. The baby is otherwise well and thriving. The eosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis, gastritis, gastroenteritis and colitis. While in children symptoms of eosinophilic esophagitis are similar to gastroesophageal reflux, in adults dysphagia and food impaction is common. Symptoms of EGIDs are generally chronically relapsing and the clinical presentation includes failure to thrive (due to chronic diarrhea, refusal of food and/or vomiting); iron deficiency anemia (due to occult or macroscopic blood loss); and hypoalbuminemia or recurrent abdominal pain.

A rare form of milk reaction is Milk-Induced Chronic Pulmonary Disease (Heiner's Syndrome), characterized by recurrent pulmonary infiltrates associated with chronic cough, recurrent fever, tachypnea, wheezing, rales, failure-to-thrive and family history of allergy caused by cow's milk ingestion.13

Natural History

Earlier studies reported a excellent overall prognosis for CMA (developing tolerance to cow's milk protein), with most children outgrowing their allergy by 3 years of age.

However, the prognosis appears to vary depending on whether the CMA is IgE-mediated or non-IgE-mediated, the titre of specific IgE at the time of diagnosis and the age of onset of CMA. The most significant factor is the nature of study. In birth cohorts, CMA was estimated to run its course within one year.41 Children with delayed reactions were found to develop tolerance sooner than those with immediate reactions, and these children are also less likely to develop multiple food allergy or allergy to inhalants.42 Referral, prospective studies indicate that in most cases (80 percent) tolerance is achieved within 3 to 4 years.12, 43, 44 In a cohort of pediatric patients referred to a tertiary middle in Italy for DBPCFC to cow's milk, the median duration of CMA was 23 months while 23 percent of children acquired tolerance 13 months following diagnosis and 75 percent after 43 months.

The longer duration has been found in retrospective referral studies. A study reported that less than half of the children diagnosed with IgE-mediated CMA during the first nine years of life outgrew it.45 A retrospective study involving 807 patients with IgE-meditated CMA reported resolution rates as follows: 19% by age 4 years, 42% by age 8 years, 64% by age 12 years, and 79% by 16 years.46 Children of every ages with extremely high levels of specific IgE are likely to own persistent milk allergy.

Onset of CMA in infancy has the most favorable prognosis. In persistent disease, casein sensitizationGarcia-Ara 38 and the presence of IgE against linear epitopes47 own been demonstrated.

Follow-up

Follow-up and re-evaluation of CMA is significant. Follow-up assessment should include: adherence to diet, growth monitoring, control of co-existing disorders, reinforcement of key educational messages e.g., reading food labels, preparedness for emergencies.

Periodic re-challenges should be conducted to monitor tolerance (6-12 monthly). In cases of IgE-mediated CMA, milk-specific IgE levels should also be monitored periodically. Declining levels of specific IgE correlate well with development of tolerance.14, 48 Although a specific IgE level for cows milk protein of 2ku/L has been reported to predict a 50% chance of passing a challenge test,49 systematic reviews own shown that this is not universally applicable.

References

Faced with an baby with CMA, the pediatrician must dictate an avoidance regimen. This will include a substitute; the best is – of course – breastfeeding with a mother’s diet free of milk products [1].

Breastfeeding is strongly recommended as the preferred way of baby feeding [14]. Compared to formula-fed infants, the breastfed show:

  1. Different nutritional status

  2. Different gut microflora

  3. Different growth patterns

  4. Better brain development

  5. Better immunologic system development & immune responses

  6. Fewer infections, of shorter duration.

Despite the fact that formulae are modeled after breastmilk, the human milk composition maintains its unique characteristics.

It contains a series of inimitable molecules with potential immune modulating activities. Examples comprise:

  1. cytokines (TGF-β2, IL-10, thymic stromal lymphopoietin) and chemokines, influencing the development of allergy and atopic diseases;

  2. hormones and growth factors, influencing the maturation of the baby gut and of the associated lymphoid tissues;

  3. maternal antibodies, including anti-idiotypic antibodies, capable to sustain and regulate immune cell populations through a priming of fetal and neonatal cells;

  4. PUFAs, nucleotides, glycoproteins, oligosaccharides and microRNA, capable in turn to exert immune functions.

Probably also for these reasons breastfeeding has been shown to influence a series of outcomes, including the establishment of gut microbiota, the prevention of overweight and obesity, the development of immunoallergic parameters and the neural development.

This final aspect is being actively investigated, and in the final few years offers us some new acquisitions that can be of interest in the general management of CMA.

Breastfed babies display significant structural differences in the brain anatomy compared with those that received baby formula: for instance, they present a longer corpus callosum, a higher ganglyothalamic ovoid diameter [15], a higher cortical thickness in parietal lobules [16]. Probably related to these effects, breastfeeding positively influences cognitive development and general intelligence [14].

From studies in cohorts of non-allergic infants it is known that the neural programming displays some ‘windows of plasticity’, during which environmental, nutritional, and microbiological factors may influence the brain function, generating diverse behavioral competence trajectories [17].

Numerous animal studies own focused on the effects of nutrition on brain development demonstrating that changes in dietary nutrients can alter brain morphology as well as its biochemical functions. Before the year 2010, however, much of the evidence from human studies was retrospective. Then epidemiological birth cohort studies indicated that folate, n-3 fatty acids, iodine and iron istered in pregnancy may influence the brain development in healthy children [18]. In specific, from the ALSPAC cohort we know that:

  1. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor skills, communication, and social development scores.

    For each outcome measured, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome [19]

  2. Maternal seafood intake during pregnancy of less than 340 g per week is associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ), compared with mothers who consumed more than 340 g per week [19]

  3. Iodine deficiency during pregnancy is associated with negative cognitive outcomes [19, 20].

After birth, the more implicated nutrients in the global development of infants are protein supply, PUFAs, Vitamins B12, C, A and D, iron, iodine, choline, zinc, selenium, and copper.

Independently or in combination, their nutritional availability may influence cognitive performance behavior [21]. Other studies failed to identify positive effects of breastfeeding on early life intelligence and cognitive growth from toddlerhood through adolescence [22], while an improved performance in intelligence of breastfed children was found at age 30 [23]. Taken together, the recent human studies indicate that the association among breastfeeding and improved performance in intelligence tests is not casual [24].

As a case in point, essential fatty acids frolic a central role in brain development of infants: humans can synthesize saturated and monounsaturated fatty acids but cannot synthesize the n-3 and the n-6 families of PUFA.

The parent fatty acids of these families, alpha linolenic acid (18 carbons, three double bonds with the first double bond in the n-3 position, C18:3n-3, ALA) and linoleic acid (C18:2n-6, LA) are essential fatty acids and must be present in the diet.

What formula is best for milk protein allergy

ALA is converted to eicosapentaenoic acid (C20:5 n-3, EPA) then to docosahexaenoic acid (C22:6n-3, DHA), while LA is converted to arachidonic acid (C20:4n-6, AA). DHA is a critical component of cell membranes, especially in the brain and retina. AA is both a membrane component and a precursor to potent signaling molecules, the prostaglandins and leukotrienes. The human milk always contains both AA and DHA, while in the past baby formulae had neither. Interventional studies failed to discover evidence that prenatal fish-oil (and folic acid) supplementation may influence the cognitive development of children at 6.5 y of age, but a high DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring [25].

Also, associations of maternal LC-PUFA status with kid emotional and behavioral problems were found in an epidemiologic study [26]. Nowadays, special formulae for the treatment of CMA are not in line with these characteristics of HM (Table 1).

Another significant component of breast milk is folic acid; its appropriate availability at the onset of pregnancy is associated with brain volume (Fig. 1). In children with low maternal folate levels, the head grows 0.1 mm per week less than in the controls [27].

This may translate in 1.9 million neurons and 1.9 billion synapses less per week. Low maternal folate status during early pregnancy was also found associated with a higher risk of emotional and behavioral problems in the offspring [28]. The use of prenatal folic acid supplements around the time of conception has been associated with a lower risk of autistic disorder [29]. Human milk provides sufficient folate intake, essential for normal growth and brain development; heat treatment in the breastmilk banks may critically reduce its quantity [30].

Breastfeeding also influences the gut microbiota. Its establishment soon after birth is conditioned by factors as the type of delivery (passage through the birth canal vs.

caesarean section), socioeconomic and climatic environment (born in developed vs. developing countries), and immune system development during pregnancy, antibiotic treatments, and contacts with parents, siblings and hospital staff [31]. Dietary factors (breast vs. formula feeding) are of prominent importance in this context.

The gut microbiota as a major topic of research interest in biology has increased in recent years . Studies are assessing the influence of variations in the composition of the gut microbiota on diseases, ranging from inflammation to obesity.

Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behavior. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs propose a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain [32]. It is now generally accepted that a stable gut microbiota is essential for normal gut physiology and contributes to appropriate signaling along the gut–brain axis and, thereby, to the healthy status of the individual, as shown on the left-hand side of Fig.

2. The right-hand side of the figure indicates how intestinal dysbiosis can adversely influence gut physiology, leading to inappropriate gut–brain axis signaling and associated consequences for CNS functions and resulting in disease states. Conversely, stress at the level of the CNS can affect gut function and lead to perturbations of the microbiota [33]. Thus, the emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complicated CNS disorders.

Of course, every these activities of breastfeeding are mediated through epigenetic activities of the diet, especially during prenatal and early postnatal life.

Diets high in choline, methionine, folate, vitamin B6 and vitamin B12 increase DNA and histone methylation altering gene expression and generating permanent changes in development [34]. Early-life nutritional exposures, therefore, can act on the development of asthma, allergy, and obesity through epigenetic mechanisms [35].

Cow’s Milk Allergy in Children

Editor's Note: The "Cow's Milk Allergy in Children" manuscript was submitted by the tardy Cassim Motala, MD and kindly updated and completed on his behalf by Alessandro Fiocchi, MD. Professor Motala was a member of the WAO Web Editorial Board and contributed his time and knowledge of pediatric allergy to numerous of WAO's initiatives.

Posted: October 2011
Updated: July 2012

Cassim Motala, MD
School of Kid & Adolescent Health
University of Cape Town and Red Cross War Memorial Children's Hospital
Capetown, South Africa
Alessandro Fiocchi, MD
Paediatric Division
Department of Kid and Maternal Medicine
University of Milan Medical School at the Melloni Hospital
Milan, Italy

Treatment of Cow's Milk Allergy in Children

Specific oral tolerance induction

Avoidance is hard as cow's milk protein is ubiquitous and accidental allergic reactions in children with CMA are common.nowak, 22 Specific oral tolerance induction (SOTI) or desensitization is a promising therapy for IgE-mediated.39 Randomized controlled trials own reported that about 35% of children become fully tolerant to cow's milk protein after SOTI; 15-20% may not finish the procedure because of severe adverse reactions; no fatal events own been documented.

Follow-up data on children who became tolerant to cow's milk protein is inadequate and it is unclear where tolerance is transient on permanent.40 Patients undergoing SOTI require careful monitoring. Various protocols own been described, some audacious and some prudent and the procedure is extremely time consuming. For these reasons, SOTI should be regarded for now as experimental therapy and must only be undertaken by practitioners who own been trained in this procedure.1

Conclusions

Cow's milk allergy is one of the most frequent manifestations of food allergy and may present as an IgE- or non-IgE-mediated disease.

Patients with IgE-mediated CMA and asthma are at risk of potentially severe allergic reactions (anaphylaxis). The diagnosis of CMA relies primarily on clinical evaluation supported by skin prick testing and in vitro measurement of specific IgE. CMA can be adequately treated with dietary manipulation including avoidance cow's milk protein products. Every cases of CMA must be managed in collaboration with an experienced dietician who has expertise in food allergy.

The dietician's role is to provide advice/recipes/education (reading food labels, checking for hidden ingredients, etc.) and to ensure nutritional adequacy. The condition can be handled at the primary level, but whenever possible it should be referred to a specialist with expertise in allergy. This becomes mandatory in severe cases of cow's milk allergy.

Diagnosis

Immediate reactions

These happen <2 hours after ingestion. The most frequent manifestations are IgE-mediated cutaneous (urticaria, angioedema, acute flare-up of atopic eczema) and gastrointestinal (vomiting, diarrhea, colic) reactions.

Cow's milk protein-induced enterocolitis syndrome is an immediate-onset, non-IgE-mediated, condition. It is characterized by initial symptoms occurring during the first months of life as repeated vomiting episodes sometimes leading to dehydration. Symptoms might be extremely severe and mimic sepsis. A characteristic feature of this syndrome is a symptom free interval of up to several hours between ingestion of milk, most often a cow's milk protein-based formula, and the first symptoms.4 Respiratory manifestations (asthma, allergic rhinitis) are infrequent, especially as isolated symptoms.

There is a belief among some members of the lay public that the consumption of milk and dairy products increases the production of mucus in the respiratory tract – there is no scientific confirmation of this.5 Anaphylaxis is the most severe manifestation. Currently defined as "a severe systemic or generalised severe allergic reaction",6 this potentially life-threatening condition greatly adds to the burden of living with milk allergy. Diagnostic criteria include sudden onset involving skin, mucosa, or both, with at least one respiratory symptom such as dyspnoea, bronchospasm, stridor, PEF reduction, hypoxemia, drop in blood pressure, organ dysfunction symptoms (hypotonia, syncope, etc), gastrointestinal symptoms (colic, vomiting) and shock.7 This happens almost immediately (within minutes and up to two hours) after the ingestion of cow's milk or dairy products and is clinically similar to anaphylaxis from foods diverse from CM.8

Milk substitutes not recommended for treatment of CMA

Partially-hydrolyzed formulae (pHF) are contra-indicated in the treatment of CMA because of the high content of residual allergen (only 12-26% of cow's milk protein is hydrolyzed in the currently available pHFs) and a definite risk of allergic reactions to these products.

By definition, they do not meet the AAP standards for hypoallergenicity. Goat, sheep, buffalo, horse milk, and whole rice milk are also not recommended — these milks are not nutritionally adequate and often cross-react with proteins in cow's milk.

Alternate formula (milk substitutes)
See Table 1

The recently published international guidelines1, kemp recommend extensively hydrolyzed formulae (eHF) or amino-acid based formulae (AAF) as first line alternatives for children with CMA.

In general, eHFs are nutritionally adequate and well-tolerated by children allergic to cow's milk and other foods but their main drawbacks are their bitter taste, expense (2-3 times the cost of standard formula), and their potential to cause anaphylaxis. As such formula are obtained from casein or whey proteins, residual antigenic activity has been found in every types of extensive hydrolysates by both in vitro and in vivo studies, which show that any formula may potentially trigger reactions in infants allergic to cow's milk.35 Current guidelines define a therapeutic formula as one that is tolerated by at least 90% (with 95% confidence) of CMPA infants.36 The antigenicity and allergenicity of hydrolysate formulae is partially dependent on their molecular weight, even if prevention studies protest that formulae with a higher mean molecular weight may be associated with a better outcome in prevention of CMA,37 and the definition of hypoallergenic formula does not rely on the molecular weight.

Rice-hydrolized formula (RHF) are considered a second-line resource due to their not universal availability.1 Where available, RHF can be considered instead of eHF. AAFs are safe and palatable but are exorbitantly expensive (6-8 times the cost of eHFs) and not widely available. Reimbursement for AAFs by health funders is also a potential problem as they are not generally considered as therapeutic agents. Soy formula is well tolerated in up to 85% of infants with IgE-mediated CMA but only in 50% of those with non-IgE mediated CMA. However, soya is not recommended in infants under 6 months because of concerns about possible hormonal effects on the reproductive system (shown in animal studies)- presumed due to phyto-oestrogens in the form of isoflavones (genistein,diadzen and their glycosides) present in soya protein.

To date, no studies own evaluated safety of soya formula in humans-such studies are much needed.

Table 1. Choosing the appropriate substitute formula in diverse presentations1

Clinical presentation 1st choice 2nd choice 3rd choice
Anaphylaxis AAF+ eHF SF
Immediate gastrointestinal allergy eHF§♭ AAF^/SF°
Food protein-induced enterocolitis syndrome (FPIES) AAF eHF*
Asthma and rhinitis eHF§♭ AAF^/SF°
Acute urticaria or angioedema eHF§♭ AAF^/SF°
Atopic dermatitis eHF§♭ AAF^/SF°
Gastroesophageal reflux disease (GERD) eHF AAF
Allergic eosinophilic oesophagitis AAF
Cow's milk protein-induced enteropathy eHF§♭ AAF
Constipation eHF AAF Donkey milk
Severe irritability (colic) eHF AAF
CM protein-induced gastroenteritis and proctocolitis eHF AAF
Milk-induced chronic pulmonary disease (Heiner's syndrome) ** AAF^ SF eHF

+ recommendation 7.1
recommendation 7.2
* if AAF refusal
§ subject to local availability, HRF can be considered instead than eHF (7.4)
# subject to a negative SPT with the specific formula (panel recommendation)
^ AAF if a relatively high worth on avoiding sensitization by SF and/or a low worth on resource expenditure are placed.
° SF if a relatively low worth on avoiding sensitization by SF and/or a high worth on resource expenditure are placed.
** this suggestion attributes a high worth on avoiding exposure to even residual antigenic cow's milk proteins.
based on reports from one case series38
+given that more than 50% of such children are allergic to soy, a careful clinical evaluation is necessary (panel recommendation)1

Avoidance of cow's milk protein

Patients with cow's milk allergy must strictly avoid cow's milk and cow's milk protein-based products.

Patients and their families must be instructed to read labels and identify milk-containing products. Particularly in young children, a well-balanced diet with sufficient intake of calcium and other essential nutriments must be warranted. The input of a paediatric dietician is most helpful in these patients. Mothers of breast-fed infants with CMA should continue breast-feeding but avoid causal foods. Recent studies lift the question of the possibility of following an incomplete milk avoidance in less severe cases of CMA.

Children receiving limited, extensively heated milk reported no acute milk-induced allergic reactions as a result of this diet, suggesting that a change from a milk avoidance diet to a milk-limited diet could provide a substantial improvement to the quality of life of milk-allergic individuals.26, 27 Moreover, baked milk tolerant consuming baked products own been recently indicated more likely to own unheated milk tolerance than subjects not consuming such products.28 This is in conflict with the observation that CMA children exposed to little doses of milk proteins in eHF may display a longer duration of CMA.29 Thus, exposing such children to milk allergens remains an unwarranted practice.

The literature does not report a single case of an adverse reaction to lactose ingestion among children with CMA, and a prospective study of the allergenicity of whey-derived lactose investigated by serology and DBPCFC did not document such reactions.30 Thus, even if lactose ingestion may per se carry risks of cow's milk protein contamination (as seen from incidents after inhalation of lactose-containing drugs31) the entire elimination of lactose from the diet of children with CMA is not warranted.

Conversely, beef allergy is possible in children with CMA.32 While almost every children allergic to beef are also allergic to milk,33 industrial treatment, more than home cooking, may modify the allergic reactivity of this meat in beef-sensitive children,34 thus making industrially freeze-dried or homogenized beef safe alternatives to butcher's meat cooked at home.

Again thus, although beef allergy should be considered, entire avoidance of beef by every children allergic to cow's milk is not justified.

Clinical evaluation

A comprehensive history (including a family history of atopy) and careful physical examination form the foundation for the diagnosis and management of CMA. Unfortunately, there is not one symptom that is pathognomonic for cow's milk allergy, but the timing and pattern of symptoms aid the diagnosis. For instance, in a patient that presents an acute anaphylaxis after ingestion of milk without another food or trigger, there is a extremely strong clinical suspicion. Symptoms of CMA happen often, but not always, within the first weeks after the introduction of cow's milk proteins.

Numerous of the children with cow's milk allergy develop symptoms in at least two of the following organ systems: gastrointestinal (50-60%), skin (40-50%) and respiratory tract. Temporal relationship between milk ingestion and onset of symptoms should also be assessed to distinguish immediate from non-IgE-mediated reactions.

Diagnostic tests

IgE-mediated CMA. Skin-prick testing (SPT) with unused milk or commercial reagents and ImmunoCAP-RAST (for determining specific IgE against cow's milk proteins as caseins, lactoglobulin, and alpha-lactalbumin), are the currently available tests.

The performance characteristics of these tests own been described in diverse settings. In children older than two years, an SPT reaction with a wheal diameter ≥8mm14 or milk specific IgE level ≥15,0 ku/L, the likelihood is 95% that the kid will own a positive milk challenge. The corresponding wheal size in children younger than two years is 6mm diameter5 and milk-specific IgE ≥5,0ku/L16 respectively.

What formula is best for milk protein allergy

Studies on specific caseloads are limited by several factors inherent to the characteristics of the studied group, such as clinical conditions (AD, asthma, GI), their severity, the percentage of polyallergic patients, and age and geographical differences.17 Thus, the use of sensitization tests is dependent on the clinical setting and on the pre-test probability of disease. For this reason, the whole matter has been subjected to systematic review and metanalysis in the preparation of the Diagnosis and Rationale Against Cow's Milk Allergy (DRACMA) guidelines. Including studies published up to September 2009, the DRACMA panel reviewed the evidence summaries and the draft guidelines, and made recommendations on diagnosis.

According to these recommendations,

  1. Hill DJ, Firer MA, Ball G, Hosking CS.

    Natural history of cow's milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy 1993; 23: 124-31.

  2. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120:1172-7
  3. Bahna SL. Blind food challenge testing with wide-open eyes. Ann Allergy 1994, 72: 235-8.
  4. Moissidis I, Chaidaroon D, Vichyanond P, Bahna SL. Milk-induced pulmonary disease in infants (Heiner syndrome).

    Pediatr Allergy Immunol 2005;16:545-52

  5. Muraro A, Roberts G, Clark A, Eigenmann PA, Halken S, Lack G, Moneret-Vautrin A, Niggemann B, Rancé F. The management of anaphylaxis in childhood: position paper of the European Academy of allergy and clinical immunology. Allergy 2007; 62:857-71
  6. Hill DJ, Heine RG, Hosking CS, Brown J, Thiele L, Allen KJ, Su J, Varigos G, Carlin JB.IgE food sensitization in infants with eczema attending a dermatology department.J Pediatr 2007;151:359-63.
  7. Simons FE, Ardusso LR, Bilò MB, El-Gamal YM, Ledford DK, Ring J, Sanchez-Borges M, Senna ge, Sheikh A, Thong B for the World Allergy Organization. World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis.

    World Allergy Organization Journal 2011; 4: 13-37

  8. Terracciano L, Bouygue G, Sarratud T, Veglia F, Martelli A, Fiocchi A. Impact of dietary regimen on the duration of cow's milk allergy. a random allocation study. Clin Exp Allergy 2010; 40:637-42
  9. Mehl A., Rolinck-Werninghaus C., Staden U., Verstege A., Wahn U., Beyer K., Niggemann B. The atopy patch test in the diagnostic workup of suspected food-related symptoms in children J Allergy ClinImmunol 2006;118:923-9
  10. Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA.

    Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol 2004;113:558-60.

  11. Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome. J Pediatr 1990; 116:862-7.
  12. Fiocchi A, Restani P, Riva E, Mirri GP, Santini I, Bernardo L, Galli CL. Heat treatment modifies the allergenicity of beef and bovine serum albumin. Allergy, 1998; 53:798-802
  13. Høst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K.

    Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood. Pediatr. Allergy Immunol. 2002;3:23-28;

  14. Savilahti E. Food-induced malabsorption syndromes. J Pediatr Gastroenterol Nutr 2000; 30 Suppl: S61-S66
  15. Werfel SJ, Cooke SK, Sampson HA. Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol 1997; 99:293-300
  16. Caminiti L, Passalacqua G, Barberi S, Vita D, Barberio G et al. A new protocol for specific oral induction in children with IgE-mediated cow's milk allergy.

    Allergy Asthma Proc 2008;30:443-8

  17. It should be performed with physician supervision regardless of food-specific IgE value.
  18. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW.

    Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391-7.

  19. In such settings, a negative SPT and/or ImmunoCAP with whole milk (cut-off: 0.35 kUI/L) can be used as rule-out tests in case of low pre-test probability.
  20. In settings where oral food challenge is not considered a requirement for making a diagnosis of IgE-mediated cow's milk allergy, a positive SPT and/or ImmunoCAP (cut-off: 0.35 kUI/L) can be used and diagnostic tests in case of high pre-test probability.
  21. Nowak-Wegrzyn A et al.

    Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol 2008, 122:342-7

  22. If challenge is positive, out of a research setting sensitization tests may not be necessary.
  23. Powell GK. Milk-and soy-induced enterocolitis of infancy. J Pediatr 1978;93:553-60
  24. In any case of high uncertainty, challenges remain necessary.
  25. Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast -fed infants. J Pediatr 1982;101:906-10
  26. Järvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ Sampson HA. B-cell epitopes as a screening instrument for persistent cow's milk allergy, J. Allergy Clin Immunol 2002;110:293-7
  27. Longo G, Barbi E, Berti I, et al.

    Specific oral tolerance induction in children with extremely severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008;121:343-347.

  28. Miceli Sopo S et al. The predictive worth of specific immunoglobulin E levels for the first diagnosis of cow's milk allergy. A critical analysis of pediatric literature. Pediatr Allergy Immunol 2007; 18:575-82
  29. Novembre E, Vierucci A. Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy 2001;56 Suppl 67:105-8.
  30. Vanto T, Helppila S, Juntunen-Backman K, et al. Prediction of the development of tolerance to milk in children with cow milk hypersensitivity.

    J Pediatr 2004:144: 218-22.

  31. Kim JS et al. Dietary baked milk accelerates the resolution of cow's milk allergy in children. J Allergy Clin Immunol. 2011;128:125-131
  32. Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS; Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology. Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009;123(6 Suppl):S365-83
  33. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA.

    Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998: 101: e8.

  34. Celik-Bilgili S, Mehl A, Verstege A et al. The predictive worth of specific immunoglobulin E levels in serum for the outcome of oral food challenges, Clin Exp Allergy 2005;35:26-73
  35. Iacono G, Carroccio A, Cavataio F, Montalto G, Soresi M, Balsamo V. Use of ass's milk in multiple food allergy. J Pediatr Gastroenterol Nutr 1992, 14:177-181
  36. Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011;127:647-53
  37. A formal challenge with cow's milk remains the best diagnostic test.
  38. Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K.

    Specific oral tolerance induction in food allergy in children: Efficacy and clinical patterns of reaction. Allergy. 2007;62:1261-1269.

  39. Fiocchi A, Bouygue GR, Albarini M, Restani P. Molecular diagnosis of cow's milk allergy. Curr Opin Allergy Clin Immunol. 2011;11:216-21
  40. Fiocchi A, Restani P, Leo G, Martelli A, Bouygue GR, Terracciano L, Ballabio C, Valsasina R. Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics. 2003; 112:359-6
  41. von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grübl A, Wichmann HE, Bauer CP, Reinhardt D, Berdel D; German Baby Nutritional Intervention Study Group.

    Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Baby Nutritional Intervention Study. J Allergy Clin Immunol. 2007;119:718-25

  42. Terracciano L, Isoardi P, Arrigoni S, Zoja A, Martelli A. Milk, Soy and Rice Hydrolysates. Ann Allergy, Asthma & Immunology 2002;89: 86-90
  43. Martelli A, De Chiara A, Corvo M, Restani P, Fiocchi A. Beef allergy in children with cow's milk allergy. Cow's milk allergy in children with beef allergy. Ann Allergy, Asthma Immunol 2002;89: S38-43
  44. Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children.

    Clin Exp Allergy 2000;30:1540-6

  45. American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic baby formulas. Pediatrics 2000;106:346-9.
  46. Skripak JM et al. Mammalian milk allergy: avoidance strategies and oral desensitization. Curr Opin Allergy Clin Immunol. 2009;9:259-64
  47. Fiocchi A, Brozek J, Schunemann HJ, Bahna SL, von Berg A, Beyer K, et al. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. WAO Journal 2010; 3:57-61
  48. Fiocchi A, Terracciano L, Bouygue GR, Veglia F, Sarratud T, Martelli A, Restani P. Incremental prognostic factors associated with cow's milk allergy outcomes in baby and kid referrals: the Milan Cow's Milk Allergy Cohort study.

    Ann Allergy Asthma Immunol. 2008;101:166-73

  49. García-Ara MC, Boyano-Martínez MT, Díaz-Pena JM, Martín-Muñoz MF, Martín-Esteban M. Cow's milk-specific immunoglobulin E levels as predictors of clinical reactivity in the follow-up of the cow's milk allergy infants. Clin Exp Allergy. 2004;34:866-70;
  50. Niggemann B, Sielaff B, Beyer K, Binder C, Wahn U. Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy 1999; 29: 91-6.
  51. Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, et al. Specific IgE levels in the diagnosis of immediate hypersensitivity to cow's milk protein in the baby.

    J Allergy Clin Immunol 2001: 107: 185-90

  52. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001: 107: 891-6
  53. Levy Y, Segal N, Garty B, Danon YL. Lessons from the clinical course of IgE-mediated cow milk allergy in Israel. Pediatr Allergy Immunol 2007: 18: 589-93
  54. Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U. Standardization of food challenges in patients with immediate reactions to foods-position paper from the European Academy of Allergology and Clinical Immunology. Allergy 2004;59:690-7
  55. Perry TT, Matsui EC, Kay Conover-Walker M.

    Wood RA. The relationships of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol 2004;114:144-9

The prognostic and diagnostic utility of using specific proteins at ImmunoCAP or microarrayed platforms remains to be established.18

Non-IgE-mediated CMA: There are no dependable tests for the diagnosis of non-IgE mediated CMA. Initial diagnosis is based on a suggestive history and absence of positive SPT or ImmunoCAP-RAST. In these patients, the diagnosis primarily relies on a successful milk avoidance diet with clinical relapses after re-exposure to cow's milk proteins.

In patients with atopic dermatitis and eosinophil esophagitis in whom non-IgE mediated cow's milk allergy is suspected, Atopy Patch testing (APT) may be a helpful diagnostic tool.19

Elimination-challenge testing: Food challenges remain the definitive procedure for the diagnosis of CMA. If the symptoms substantially improve or vanish after 2-4 weeks on an elimination diet, an open challenge with a formula based on whole cow's milk protein should be performed.

Clinicians should be aware that the severity of a past reaction might not predict the severity of a challenge reaction, particularly after a period of dietary exclusion. Previous mild reactions may be followed by anaphylactic reactions in some infants with CMA. For this reason, open challenges should ideally be performed in a setting where resuscitation facilities are available. In a case of cow's milk-induced anaphylaxis, a challenge is contraindicated unless SPTs and/or specific IgE measurements show improvement. In these cases, the challenge should always be performed in a hospital setting.

Positive challenge: CMA confirmed

If symptoms of CMA re-appear, the suspected diagnosis of CMA is confirmed and the baby should be maintained on an elimination diet using a milk substitute (discussed below) for at least 6 months.

The challenge is then repeated. If it is possible to follow the baby with IgE-mediated allergy with SPTs and/ or specific IgE determination, improvement of these tests would assist in choosing the time point of challenge. Supplementary feeding should be introduced carefully to avoid accidental intake of cow's milk protein. Protocols of milk challenges own been published in diverse guidelines.1, 20, 21 Of importance, every guidelines emphasize the rules for milk challenge in immediate CMA, while the interpretation of delayed reactions occurring up to 7,22 9,23 or 14 days24 is more controversial.

The diagnosis of delayed reaction may be hard because when the kid returns home, multiple environmental factors (infections, dietary factors, emotional, casual contacts, sports-related physical activity) may impinge diagnostic interpretation. Frequently, immediate and delayed symptoms are present concomitantly in the same child.25

Negative challenge: No CMA

Children who do not develop symptoms on the cow's milk formula during challenge and up to one week after follow-up can resume their normal diet, although they should still be carefully monitored. Clinicians should advise parents to be attentive for delayed reactions, which may evolve over several days following the challenge.

Pathogenesis

CMA results from an immunological reaction to one or more milk proteins.

This immunological basis distinguishes CMA from other adverse reactions to cow's milk protein such as lactose intolerance. CMA may be immunoglobulin E (IgE) or non-IgE-mediated and may be a manifestation of the atopic diatheses and multiple food allergies. Reactions to other foods (depending on the regional dietary intake) may happen in combination with CMA. Non-IgE-mediated disorders generally involve T-Cells (or eosinophils), present mainly with gastrointestinal symptoms and are less likely to develop multiple food allergies. IgE- and non-IgE-mediated mechanisms may frolic a role in the pathogenesis of atopic dermatitis and the eosinophilic gastrointestinal disorders (EGIDs).

Introduction

The estimated prevalence of cow's milk allergy (CMA) varies between 0.25% and 4.9%, being higher in children than adults.1 The prevalence is higher in referral populations, depending on the nature of the basic condition.

For instance, in a consecutive series with moderate atopic eczema referred to a University-affiliated dermatology department, SPT showed 16% of infants with IgE against CMP.2 In a group of infants and children with AD and no other allergic manifestations, 37% had a diagnosis of CMA.3 Cow's milk allergy can develop in exclusively or partially breast-fed infants, when cow's milk protein is introduced into the feeding regime. The incidence of CMA is lower in exclusively breast-fed infants compared to formula-fed or mixed-fed infants, and clinical reactions in the breast-fed group are mostly mild to moderate.

This might be related to lower levels of CMP in breast milk compared to cow's milk. Immunomodulators in breast milk and differences in gut flora between breast-fed and formula-fed infants may also frolic a role.

Clinical Manifestations

The clinical manifestations of CMA depend to a grand extent on the type of immunological reaction involved.

Delayed reactions

These immunological, non-IgE-mediated reactions happen several hours or days after milk consumption. Atopic dermatitis is observed in approximately 10-15% of young children. It is primarily because of the dryness of skin and is linked to hereditary factors; however, approximately one third of patients with moderate to severe atopic dermatitis present with flares of eczema linked to a food allergy.9 Cow's milk, hen's egg, and peanuts are the foods most frequently involved.

GI disorders include food protein-induced (FPI) enterocolitis, enteropathy and proctolitis.10 Milk induced proctocolitis is mostly observed in young infants while exclusively breast-fed.11 FPI disorders are typically cow's milk and soya protein induced, but they may also happen with ingestion of solid foods including, fish, chicken, turkey, corn and vegetables. FPI-enterpathy generally presents with diarrhea, mild to moderate steatorrhea (80% of cases) and poor weight acquire. The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.12 Rectal bleeding is the usual presenting feature of FPI-colitis.

The baby is otherwise well and thriving. The eosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis, gastritis, gastroenteritis and colitis. While in children symptoms of eosinophilic esophagitis are similar to gastroesophageal reflux, in adults dysphagia and food impaction is common. Symptoms of EGIDs are generally chronically relapsing and the clinical presentation includes failure to thrive (due to chronic diarrhea, refusal of food and/or vomiting); iron deficiency anemia (due to occult or macroscopic blood loss); and hypoalbuminemia or recurrent abdominal pain.

A rare form of milk reaction is Milk-Induced Chronic Pulmonary Disease (Heiner's Syndrome), characterized by recurrent pulmonary infiltrates associated with chronic cough, recurrent fever, tachypnea, wheezing, rales, failure-to-thrive and family history of allergy caused by cow's milk ingestion.13

Natural History

Earlier studies reported a excellent overall prognosis for CMA (developing tolerance to cow's milk protein), with most children outgrowing their allergy by 3 years of age. However, the prognosis appears to vary depending on whether the CMA is IgE-mediated or non-IgE-mediated, the titre of specific IgE at the time of diagnosis and the age of onset of CMA.

The most significant factor is the nature of study. In birth cohorts, CMA was estimated to run its course within one year.41 Children with delayed reactions were found to develop tolerance sooner than those with immediate reactions, and these children are also less likely to develop multiple food allergy or allergy to inhalants.42 Referral, prospective studies indicate that in most cases (80 percent) tolerance is achieved within 3 to 4 years.12, 43, 44 In a cohort of pediatric patients referred to a tertiary middle in Italy for DBPCFC to cow's milk, the median duration of CMA was 23 months while 23 percent of children acquired tolerance 13 months following diagnosis and 75 percent after 43 months.

The longer duration has been found in retrospective referral studies. A study reported that less than half of the children diagnosed with IgE-mediated CMA during the first nine years of life outgrew it.45 A retrospective study involving 807 patients with IgE-meditated CMA reported resolution rates as follows: 19% by age 4 years, 42% by age 8 years, 64% by age 12 years, and 79% by 16 years.46 Children of every ages with extremely high levels of specific IgE are likely to own persistent milk allergy.

Onset of CMA in infancy has the most favorable prognosis. In persistent disease, casein sensitizationGarcia-Ara 38 and the presence of IgE against linear epitopes47 own been demonstrated.

Follow-up

Follow-up and re-evaluation of CMA is significant. Follow-up assessment should include: adherence to diet, growth monitoring, control of co-existing disorders, reinforcement of key educational messages e.g., reading food labels, preparedness for emergencies. Periodic re-challenges should be conducted to monitor tolerance (6-12 monthly). In cases of IgE-mediated CMA, milk-specific IgE levels should also be monitored periodically.

Declining levels of specific IgE correlate well with development of tolerance.14, 48 Although a specific IgE level for cows milk protein of 2ku/L has been reported to predict a 50% chance of passing a challenge test,49 systematic reviews own shown that this is not universally applicable.

References

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    Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol 2008, 122:342-7

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  • Martelli A, De Chiara A, Corvo M, Restani P, Fiocchi A. Beef allergy in children with cow's milk allergy. Cow's milk allergy in children with beef allergy. Ann Allergy, Asthma Immunol 2002;89: S38-43
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    Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Baby Nutritional Intervention Study. J Allergy Clin Immunol. 2007;119:718-25

  • Caminiti L, Passalacqua G, Barberi S, Vita D, Barberio G et al. A new protocol for specific oral induction in children with IgE-mediated cow's milk allergy. Allergy Asthma Proc 2008;30:443-8
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  • Savilahti E. Food-induced malabsorption syndromes. J Pediatr Gastroenterol Nutr 2000; 30 Suppl: S61-S66
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    Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol 1997; 99:293-300

  • Celik-Bilgili S, Mehl A, Verstege A et al. The predictive worth of specific immunoglobulin E levels in serum for the outcome of oral food challenges, Clin Exp Allergy 2005;35:26-73
  • Levy Y, Segal N, Garty B, Danon YL. Lessons from the clinical course of IgE-mediated cow milk allergy in Israel.

    Pediatr Allergy Immunol 2007: 18: 589-93

  • Skripak JM et al. Mammalian milk allergy: avoidance strategies and oral desensitization. Curr Opin Allergy Clin Immunol. 2009;9:259-64
  • Fiocchi A, Restani P, Riva E, Mirri GP, Santini I, Bernardo L, Galli CL. Heat treatment modifies the allergenicity of beef and bovine serum albumin. Allergy, 1998; 53:798-802
  • Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998: 101: e8.
  • Bishop JM, Hill DJ, Hosking CS.

    Natural history of cow milk allergy: clinical outcome. J Pediatr 1990; 116:862-7.

  • Muraro A, Roberts G, Clark A, Eigenmann PA, Halken S, Lack G, Moneret-Vautrin A, Niggemann B, Rancé F. The management of anaphylaxis in childhood: position paper of the European Academy of allergy and clinical immunology. Allergy 2007; 62:857-71
  • Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS; Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology. Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009;123(6 Suppl):S365-83
  • American Academy of Pediatrics.

    Committee on Nutrition. Hypoallergenic baby formulas. Pediatrics 2000;106:346-9.

  • Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, et al. Specific IgE levels in the diagnosis of immediate hypersensitivity to cow's milk protein in the baby. J Allergy Clin Immunol 2001: 107: 185-90
  • Niggemann B, Sielaff B, Beyer K, Binder C, Wahn U. Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy 1999; 29: 91-6.
  • Kim JS et al. Dietary baked milk accelerates the resolution of cow's milk allergy in children. J Allergy Clin Immunol. 2011;128:125-131
  • Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children.

    Clin Exp Allergy 2000;30:1540-6

  • Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001: 107: 891-6
  • Fiocchi A, Terracciano L, Bouygue GR, Veglia F, Sarratud T, Martelli A, Restani P. Incremental prognostic factors associated with cow's milk allergy outcomes in baby and kid referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol. 2008;101:166-73
  • Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M.

    The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011;127:647-53

  • Longo G, Barbi E, Berti I, et al. Specific oral tolerance induction in children with extremely severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008;121:343-347.
  • Fiocchi A, Brozek J, Schunemann HJ, Bahna SL, von Berg A, Beyer K, et al. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. WAO Journal 2010; 3:57-61
  • Fiocchi A, Restani P, Leo G, Martelli A, Bouygue GR, Terracciano L, Ballabio C, Valsasina R.

    Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics. 2003; 112:359-6

  • Hill DJ, Heine RG, Hosking CS, Brown J, Thiele L, Allen KJ, Su J, Varigos G, Carlin JB.IgE food sensitization in infants with eczema attending a dermatology department.J Pediatr 2007;151:359-63.
  • Novembre E, Vierucci A. Milk allergy/intolerance and atopic dermatitis in infancy and childhood. Allergy 2001;56 Suppl 67:105-8.
  • Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120:1172-7
  • Järvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ Sampson HA. B-cell epitopes as a screening instrument for persistent cow's milk allergy, J.

    Allergy Clin Immunol 2002;110:293-7

  • Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast -fed infants. J Pediatr 1982;101:906-10
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  • Hill DJ, Firer MA, Ball G, Hosking CS. Natural history of cow's milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy 1993; 23: 124-31.
  • Miceli Sopo S et al.

    The predictive worth of specific immunoglobulin E levels for the first diagnosis of cow's milk allergy. A critical analysis of pediatric literature. Pediatr Allergy Immunol 2007; 18:575-82

  • Perry TT, Matsui EC, Kay Conover-Walker M. Wood RA. The relationships of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol 2004;114:144-9

Not to be confused with Lactose intolerance.

Milk allergy is an adverse immune reaction to one or more proteins in cow’s milk. When allergy symptoms happen, they can happen rapidly or own a gradual onset. The previous may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine among other measures.

The latter can take hours to days to appear, with symptoms including atopic dermatitis, inflammation of the esophagus, enteropathy involving the little intestine and proctocolitis involving the rectum and colon.[2]

In the United States, 90% of allergic responses to foods are caused by eight foods, with cow’s milk being the most common.[3] Recognition that a little number of foods are responsible for the majority of food allergies has led to requirements to prominently list these common allergens, including dairy, on food labels.[4][5][6][7] One function of the immune system is to defend against infections by recognizing foreign proteins, but it should not over-react to food proteins.

Heating milk proteins can cause them to become denatured, meaning to lose their 3-dimensional configuration, and thus lose allergenicity; for this reason dairy-containing baked goods may be tolerated while unused milk triggers an allergic reaction.

Management is by avoiding eating any dairy foods or foods that contain dairy ingredients.[8] In people with rapid reactions (IgE-mediated milk allergy), the dose capable of provoking an allergic response can be as low as a few milligrams, so recommendations are to avoid dairy strictly.[9][10] The declaration of the presence of trace amounts of milk or dairy in foods is not mandatory in any country, with the exception of Brazil.[5][11][12]

Milk allergy affects between 2% and 3% of babies and young children.[8][13] To reduce risk, recommendations are that babies should be exclusively breastfed for at least four months, preferably six months, before introducing cow’s milk.

If there is a family history of dairy allergy, then soy baby formula can be considered, but about 10 to 15% of babies allergic to cow’s milk will also react to soy.[14] The majority of children outgrow milk allergy, but for about 0.4% the condition persists into adulthood.[15]Oral immunotherapy is being researched, but it is of unclear benefit.[16][17]

Not to be confused with Lactose intolerance.

Milk allergy is an adverse immune reaction to one or more proteins in cow’s milk. When allergy symptoms happen, they can happen rapidly or own a gradual onset. The previous may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine among other measures.

The latter can take hours to days to appear, with symptoms including atopic dermatitis, inflammation of the esophagus, enteropathy involving the little intestine and proctocolitis involving the rectum and colon.[2]

In the United States, 90% of allergic responses to foods are caused by eight foods, with cow’s milk being the most common.[3] Recognition that a little number of foods are responsible for the majority of food allergies has led to requirements to prominently list these common allergens, including dairy, on food labels.[4][5][6][7] One function of the immune system is to defend against infections by recognizing foreign proteins, but it should not over-react to food proteins.

Heating milk proteins can cause them to become denatured, meaning to lose their 3-dimensional configuration, and thus lose allergenicity; for this reason dairy-containing baked goods may be tolerated while unused milk triggers an allergic reaction.

Management is by avoiding eating any dairy foods or foods that contain dairy ingredients.[8] In people with rapid reactions (IgE-mediated milk allergy), the dose capable of provoking an allergic response can be as low as a few milligrams, so recommendations are to avoid dairy strictly.[9][10] The declaration of the presence of trace amounts of milk or dairy in foods is not mandatory in any country, with the exception of Brazil.[5][11][12]

Milk allergy affects between 2% and 3% of babies and young children.[8][13] To reduce risk, recommendations are that babies should be exclusively breastfed for at least four months, preferably six months, before introducing cow’s milk.

If there is a family history of dairy allergy, then soy baby formula can be considered, but about 10 to 15% of babies allergic to cow’s milk will also react to soy.[14] The majority of children outgrow milk allergy, but for about 0.4% the condition persists into adulthood.[15]Oral immunotherapy is being researched, but it is of unclear benefit.[16][17]


Management [10]

Challenge test

The prognosis of CMPA is excellent with a remission rate of approximately 45-50% at 1 year, 60-75% at 2 years and 85-90% at 3 years[15].Children can own a challenge test every 6-12 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.

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 10-15% 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 4.5 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.

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.

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].


Epidemiology[2, 3]

CMPA affects about 7% of formula-fed babies but only about 0.5% 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.


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 tightness.The 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.


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