Clinical features, mechanism of development of cow milk protein allergy.
Diagnostic algorithm and review of available data about cow milk protein allergy.
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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.
1/2/2017 8
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.
1/2/2017 13
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.
1/2/2017 14
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
1/2/2017 17
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
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
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 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
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?
1/2/2017 47
that allergy has become the No. 1 environmental epidemic disease facing children of the developed world.
The immunological mechanism that lead to the development
of cow’s milk allergy (or Cow’s Milk Protein
Allergy- CMPA) is not still clarified
Protein antigens may cross the epithlial barrier by transcytosis through entrecytes or uptake by microfold cells.
Paracellular diffusion.
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.
Some TLR agonists may activate Treg cells while others may trigger an allergic sensitization.
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
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
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
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
* after repeated testing for specific IgE
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.
* The available data do not support cow’s milk antigen
avoidance, and therefore, specific allergen avoidance is
not recommended during pregnancy