Clinical features, mechanism of development of cow milk protein allergy. Diagnostic algorithm and review of available data about cow milk protein allergy.

1. Cows Milk Allergy
Dr Tushar Jagzape,
Associate Professor,
AIIMS, Raipur
1/2/2017 1

2. • “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 ?”
1/2/2017 2

3. 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
1/2/2017 3

4. 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.
1/2/2017 4

5. • Food allergy is 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 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
1/2/2017 6

7. • 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%)
1/2/2017 7

8. 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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9. 1/2/2017 9

10. 1/2/2017 10
Milk induced chronic pulmonary disease (Heiner syndrome)
Faltering growth
Severe atopic eczema

11. 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
1/2/2017 12
Why we do not get allergy to food we eat?

12. 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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13. • 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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14. 1/2/2017 15

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 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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17. • Food dependent exercise induced anaphylaxis-
• Execrise – increase osmolality – histamine
release
• Reduce pH or increase GI permeability.
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18. 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
1/2/2017 20

19. 1/2/2017 21

20. 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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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 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.
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 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.
1/2/2017 27

25. 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
1/2/2017 28

26. 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
1/2/2017 29

27. 1/2/2017 30

28. 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.
1/2/2017 31

29. 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*.
1/2/2017 32

30. 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
1/2/2017 33

31. 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.
1/2/2017 34

32. 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.*
1/2/2017 35

33. 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
1/2/2017 36

34. 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.
1/2/2017 37

35. 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.
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 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.
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 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.
1/2/2017 42

40. 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
1/2/2017 43

41. • 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.
1/2/2017 44

42. 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.
1/2/2017 45

43. • 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.
1/2/2017 46

44. 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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