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Cow milk protein allergy
- 1. Cows Milk Allergy DrTushar Jagzape, Associate Professor, AIIMS, Raipur 1/2/2017 1
- 2. • “Doctor mychild 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 ?” 1/2/2017 2
- 3. Learning objectives: • Atthe 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 1/2/2017 3
- 4. Introduction • Food allergyis 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. 1/2/2017 4
- 5. • Food allergyis defined as an adverse health effect arising from a specific immune response that occurs reproducibly following exposure to a given food 1/2/2017 5
- 6. • In 2007the 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 1/2/2017 6
- 7. • Confusion betweenCMP 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%) 1/2/2017 7
- 8. Clinical presentation • Diversesymptoms. 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. 1/2/2017 8
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- 10. 1/2/2017 10 Milk inducedchronic pulmonary disease (Heiner syndrome) Faltering growth Severe atopic eczema
- 11. Mechanism of allergy. Nonspecific 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 1/2/2017 12 Why we do not get allergy to food we eat?
- 12. Mechanism of allergycont • 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. 1/2/2017 13
- 13. • Two maindescribed 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. 1/2/2017 14
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- 15. 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. 1/2/2017 16
- 16. Why are infantsat 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 1/2/2017 17
- 17. • Food dependentexercise induced anaphylaxis- • Execrise – increase osmolality – histamine release • Reduce pH or increase GI permeability. 1/2/2017 18
- 18. Probiotics and immunesystem: 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 1/2/2017 20
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- 20. Diagnostic procedures • Historyand 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 1/2/2017 22
- 21. Atopy Patch Test,Total IgE, and Intradermal Tests • 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. 1/2/2017 24
- 22. Specific IgG Antibodiesand 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. 1/2/2017 25
- 23. 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. 1/2/2017 26
- 24. Diagnostic elimination ofCMP • 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. 1/2/2017 27
- 25. Oral food challengeprocedure 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 1/2/2017 28
- 26. Type of milkand 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 1/2/2017 29
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- 28. Treatment • Strict avoidanceof 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. 1/2/2017 31
- 29. Infants upto ageof 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*. 1/2/2017 32
- 30. eHF Based onCMP • 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 1/2/2017 33
- 31. Amino acid Basedformula • 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. 1/2/2017 34
- 32. Other options • Partiallyor 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.* 1/2/2017 35
- 33. Substitute formulae thatare 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 1/2/2017 36
- 34. Weaning food • Shouldbe 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. 1/2/2017 37
- 35. Children beyond ageof 12 months • Individualized nutritional advice. • Supplementation of proteins, calcium, vitamin D and A may be required. • Therapeutic formula may be required. 1/2/2017 38
- 36. 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. 1/2/2017 39
- 37. Reevaluation • Insufficient evidenceto 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. 1/2/2017 40
- 38. 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. 1/2/2017 41
- 39. • Dietary productswith 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. 1/2/2017 42
- 40. Nutritional supplements: • Longchain 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 1/2/2017 43
- 41. • Post natalsupplementation 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. 1/2/2017 44
- 42. Summary • CMPA commonduring 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. 1/2/2017 45
- 43. • Answer toquestion 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. 1/2/2017 46
- 44. Questions unanswered • Whatis 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? 1/2/2017 47
- 45.
Editor's Notes
- #7 that allergy has become the No. 1 environmental epidemic disease facing children of the developed world.
- #15 The immunological mechanism that lead to the development of cow’s milk allergy (or Cow’s Milk Protein Allergy- CMPA) is not still clarified
- #17 Protein antigens may cross the epithlial barrier by transcytosis through entrecytes or uptake by microfold cells. Paracellular diffusion.
- #20 There are two distinct phases in the development of mucosal tolerance: the clonal deletion and the active suppression of the immune response, and it seems that Treg cells mediate both phases.
- #21 Some TLR agonists may activate Treg cells while others may trigger an allergic sensitization.
- #23 the diagnosis needs to be confirmed or excluded by an allergen elimination and challenge procedure. This can be performed as open, single-, or double-blind challenge, depending on symptoms, history, and age of the child
- #26 facial thermography and gastric juice analysis for diagnosing CMPA. In addition, hair analysis, applied kinesiology, provocation neutralization, cytotoxicity assay, and electrodermal testing should not be used for diagnosing CMPA
- #28 This ranges from 3 to 5 days in children with immediate clinical reactions (eg, angioedema, vomiting, exacerbation of eczema within 2 hours) to 1 to 2 weeks in children with delayed clinical reactions (eg, exacerbation of eczema, rectal bleeding). In patients with gastrointestinal reactions (eg, chronic diarrhea, growth faltering), it may take 2 to 4 weeks on a CMP-free diet to judge the response
- #31 If, however, diagnostic allergen elimination is effective and a subsequent CMP challenge is positive, then an allergy test may be carried out to assess the risk of an immediate reaction at later challenges and offer a prognosis for the development of tolerance
- #33 * after repeated testing for specific IgE
- #36 cow’s-milk–based formulae should be preferred over soy formula in healthy infants, and soy protein based formulae should not usually be used during the first 6 months of life - Soy formulae have nutritional disadvantages because their absorption of minerals and trace elements may be lower because of their phytate content, and they contain appreciable amounts of isoflavones with a weak estrogenic action that can lead to high serum concentrations in infants.
- #42 * The available data do not support cow’s milk antigen avoidance, and therefore, specific allergen avoidance is not recommended during pregnancy