Cow milk protein allergy

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Cows Milk Allergy

Dr Tushar Jagzape,Associate Professor,

AIIMS, Raipur

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• “Doctor my child does not eat anything except breast milk. He has started vomiting frequently since complementary feeding was started. He is also irritable and having loose motions. Is it cows milk allergy ?”

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Learning objectives:

• At the end of this session the group should be able to – Define food allergy– Describe clinical features of CMA– Describe mechanism of allergy to CMP– Apply the diagnostic algorithm– Enlist treatment options.– Describe preventive strategies for CMP

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Introduction

• Food allergy is an increasing health care concern.

• Self reported allergy – 3 to 35%• Estimated rates – using Oral Food Challenge –

1 to 10.8% • 2008 CDC report – indicated 18% increase in

childhood food allergy from 1997 -2007.

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• Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly following exposure to

a given food

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• In 2007 the World Health Organisation (WHO) acknowledged allergy epidemic.

• A review paper by the World Allergy Organization estimated that 1.9% to 4.9% of children suffer from cow's milk protein allergy (CMA).– Fiocchi A, Brozek J, Schunemann H, Bahna SL, von BA, Beyer K: World

Allergy organization (WAO) diagnosis and rationale for action against Cow's milk allergy (DRACMA) guidelines. World Allergy Organ J. 2010, 3 (4): 57-161

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• Confusion between CMP allergy and lactose intolerance.

• CMPA peaks in the first year of life and falls to <1% in children 6 years of age and older.

• Exclusive breast fed infants? • May also develop clinically significant CMPA

via dairy protein transfer into human breast milk. (0.5%)

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Clinical presentation• Diverse symptoms. Variable intensity • ‘‘Immediate’’ (early) reactions – minutes up to 2

hour.– IgE mediated

• ‘‘Delayed’’ (late) reactions. – upto 48 hours or even 1 week.– Non IgE mediated.

• It is important to remember that nonallergic reactions (eg, toxic, pharmacologic) may mimic CMPA.

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Milk induced chronic pulmonary disease (Heiner syndrome)

Faltering growth

Severe atopic eczema

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Mechanism of allergy.

Non specific mechanism• Mucosal barrier• Motility• Mucus secretion• Gastric acidity• Enzymes• Only 2% of ingested food

protein absorbed in an immunologically intact form.

Specific mechanism

• Secretary IgA• Gut associated lymphoid

tissue. (GALT)• Process food antigen and

present to MHC class II receptors.

• Oral tolerance – deletion and or inhibition of antigen specific T cells.

• Treg cells – suppress inflammation

Why we do not get allergy to food we eat?

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Mechanism of allergy cont

• The major cow’s allergens - the casein fraction of proteins (αs1-, αs2-, β-, and κ-casein) and to whey proteins (α-lactalbumin and β-lactoglobulin)

• There is some cross-reactivity with soy protein, particularly in non-IgE mediated allergy.

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• Two main described mechanisms • IgE and non IgE mediated.• Two stages – sensitization and activation • Sensitization

– genetically predisposed individual – exposure of antigen leads to TH2 type response.- Cytokines (IL4, IL 5, IL 10 and IL 13) promotes IgE production.

Activation: - Inflammatory response – eosinophils, mast cells, neutrophils and natural killers cells.

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Non IgE – mediated reactions:

• In presence of pro- inflammatory cytokines .

• Large amount of antigen reach MALT leading to IgG induction and immune complexes.

• Reactions mediated by Th1 cells, interactions between T lymphocytes, mast cells and neurons that alters the function of the smooth muscle and the intestinal motility.

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Why are infants at risk?

• Digestive enzymes are not fully active.• Immature secretory IgA.• Increased permeability of mucosa.• Undigested proteins reach immune system.• Reduced gastric acidity and intake of proton

pump inhibitors – additional risk

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• Food dependent exercise induced anaphylaxis- • Execrise – increase osmolality – histamine

release• Reduce pH or increase GI permeability.

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Probiotics and immune system:intestinal microbiota in CMPA

• Toll like receptor (TLRs) recognize specific bacterial surface markers of microbiota, so called PAMP (Pathogenassociated molecular patterns).

• A decreased microbial exposure in early life leads to T-cell dysregulation which induce allergic disorders.

• Evidences show that probiotics may promote the gut immune regulation and the allergenic tolerance

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Diagnostic procedures• History and physical examination.

• Allergen elimination and challenge procedure.

• Determination of specific IgE and skin Prick test (any one)– sIgE – sensitivity 87%, specificity – 48%– SPT – sensitivity 88% , spceificity – 68%

• These results must be interpreted in the context of medical history and food challenge procedure

• Negative test does not rule out CMPA

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Atopy Patch Test, Total IgE, and IntradermalTests

• Not recommended at present.

• No benefit of total IgE or ratio of specific IgE to total IgE over specific IgE alone.

• Intradermal skin test is risky.

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Specific IgG Antibodies and Other Nonstandardized or Unproven Tests and Procedures

• No role of IgG or subclass of IgG antibodies

• Other tests, such as basophil histamine release/activation, lymphocyte stimulation, mediator release assay and endoscopic allegen provocation are used in research protocols.

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Endoscopy and Histology

• Unexplained significant and persistent GI symptoms, failure to thrive, or iron deficiency anemia.

• Neither sensitive nor specific for CMPA.

• Helps for diagnoses other than CMPA.

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Diagnostic elimination of CMP

• Should be initiated in infant or mother.

• Immediate clinical reactions- 3-5 days

• Delayed clinical reactions- 1 to 2 weeks

• May take 2- 4 weeks for only GI symptoms (chronic diarrhea, growth faltering)

• Different recommendation for breast fed and non breast fed infant, toddlers and children.

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Oral food challenge procedure with CMP.

• After documentation of significant improvement on the diagnostic elimination, the diagnosis should be confirmed by standardized oral challenge test.

• DBPCFC – reference standrd and most specefic.

• Open challenge test

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Type of milk and dose

• First year – infant formula based on cow’s milk

• Above 12 months - fresh pasteurized milk

• Lactose free CMP containing milk – children > 3 year. (eg, in children with a delayed reaction)

• Stepwise doses of 1, 3.0, 10.0, 30.0, and 100mL may be given at 30-minute Intervals.

• If severe reactions are expected, then the challenge should begin with minimal volumes (eg, stepwise dosing of 0.1, 0.3,1.0, 3.0, 10.0, 30.0, and 100mL given at 30-minute intervals).

• If no reaction occurs, then the milk should be continued at home every day with at least 200 mL/day for at least 2 weeks

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Treatment

• Strict avoidance of CMP .

• Substitute fomula is needed to fulfill nutritional requirements in an individual child and the choice of formula depends on age and other food allergies.

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Infants upto age of 12 months

• Infant should be maintained on elimination diet using a therapeutic formula for at least 6 months or untill 9 to 12 months of age.

• Severe immediate reactions – 12 or even 18 months before rechallenge*.

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eHF Based on CMP

• Majority of infants and children tolerate extensively hydrolyzed formula.

• In addition to appropriate preclinical testing, therapeutic formulae must demonstrate in clinical studies with 95% confidence that they do not provoke allergic reactions in 90% of infants or children with confirmed cow’s-milk protein allergy

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Amino acid Based formula

• Free amino acids as the only nitrogen source.

• Best for infant reacting to eHF (risk < 10 %)

• First line – severe anaphylactic reactions and infants with severe enteropathy indicated by hypoprteinemia and faltered growth.

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Other options• Partially or extensively hydrolyzed fromula based on

rice protein.

• Refusing or not tolerating an eHF based CMP or in vegan families.

• Soy protein based formula – 10% - 14 % may react.*

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Substitute formulae that are considered to be unsafe or not nutritionally adequate in infants with CMPA

• Partially hydrolyzed formulae based on CMP or other mammalian protein .

• Industrial juices made of soy, rice, almond, coconut or chestnut – improperly called milks. Unsuitable

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Weaning food

• Should be free of CMP until supervised successful oral challenge.

• Other foods one by one along with breast feeding. Not before 17 weeks.

• Delaying introduction of higher allergenic food as egg, fish or wheat – no proven benefit.

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Children beyond age of 12 months

• Individualized nutritional advice.

• Supplementation of proteins, calcium, vitamin D and A may be required.

• Therapeutic formula may be required.

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Role of immunotherapy

• Sublingual or oral immunotherapy – Cochrane review – chances of achieving full tolerance was 10 times higher in oral immunotherapy group.

• Addition of prebiotics and probiotics speeding up development of tolerance.

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Reevaluation• Insufficient evidence to recommend an optimal interval.

• At least 3 months (specific IgE negative , mild symptoms)

• Upto 12 months (high positive IgE test or sever reaction)

• If challenge postive elimination for 6 to 12 months.

• If negative cows milk is fully reintroduced.

• Tolerence = > 50 % by 1 year, > 75% by 3 years and > 90% at 6 years of age.

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Prevention

• Allergen avoidance ?• Diet during pregnancy or lactation*• Breast feeding: – Passive – decreasing exposure to exogenous

antigens.– Active – protects against infections, maturation of

gut mucosa, healthy gut microbiota, immunomodulatory and anti-inflammatory benefits.

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• Dietary products with reduced allergenicity – – Hydrolyzed formula: extensively hydrolyzed casein

formulas and partially hydrolyzed whey formulas – reduce risk in high risk infants.

– Soy protein formula- no role in prevention.– Amino acid based formula – no studies.

• Probiotics and or prebiotics: May be effective for eczema.

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Nutritional supplements:• Long chain polyunsaturated fatty acids: Balance

between pro inflammatroy n-6 long chain polyunsaturated fatty acid (LCPUFA) and antiinflammatory n -3 –LCPUFA may play a role.

• Maternal n-3-LCPUFA during pregnancy reduced risk of atopic eczema and egg sensitization during first year. No effect on overall incidence of Ig E.

• Palmer DJ, Sullivan T, GoldMS, Prescott SL, Heddle R, Gibson RA, Makrides M (2012) Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial. Br Med J 344:e184

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• Post natal supplementation mixed results.

• Other nutritional interventions:

• Weak supportive evidence with respect to supplementation with vitamin A, D, E, Zn , fruit and vegetables for prevention of atopic asthma.

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Summary • CMPA common during 1st year of life.• Exclusively breast fed infant may be affected.• GIT, skin and respiratory system are commonly

affected.• May be IgE or non IgE mediated.• SPT may be useful. Elimination diet and OFC

test required.• Avoidance of CMP for at least 6 months helps.

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• Answer to question in the first slide- There is inadequate information to answer the question. As discussed in the presentation other symptoms and system involvement should be asked and then an appropriate decision may be taken.

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Questions unanswered

• What is the prevalence in India?• Practice of giving cows milk early is it helpful

or harmful?• What should be recommendation for

complementary diet with cows milk?

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THANK YOU!