Distinguish IgE and non-IgE mediated aspects of cow’s milk allergy (CMA) Review the clinical effects of extensively hydrolyzed formula in infants with CMA

2. ‫اآلية‬ ‫البقرة‬ ‫سورة‬32

3. COW MILK ALLERGY
22-11-2019
Khaled Saad
Professor of pediatrics

4. Cow milk allergy

5. Objectives
 Distinguish IgE and non-IgE
mediated aspects of cow’s milk
allergy (CMA)
 Review the clinical effects of
extensively hydrolyzed formula in
infants with CMA

6. A Case
Vital StatsGirl
3 months
old
Length
50th
percentile
Weight
40th
percentile
Reason for visit • Spitting up and irritability
CMA-related symptoms • Spitting up large volumes, irritability, seborrhea
Other medical history/
family history
• None
Current formula • AR formula
Feeding history • Breastmilk for 1 month, cow’s milk formula thereafter
Medications • Proton pump inhibitor
Birth history • Uncomplicated term delivery
Other considerations • Normal bowel movements

7. Vital Stats
Boy
4 months
old
Length
30th
percentile
Weight 3rd
percentile
Another Case
Reason for visit • Ongoing blood and mucus in stools
History • Poor growth
CMA-related symptoms
• Loose stools, mucus in stools, blood streaks in stools,
poor weight gain
Other medical history/
family history
• Older sister: allergy to egg
• Mother: asthma
Current formula • Intact cow’s milk–based, lactose-free formula
Feeding history
• Began on routine formula,
• Then switched to intact cow’s milk–based, lactose-free formula
Medications • Simethicone
Birth history • Uncomplicated term delivery
Other considerations • Gassiness
t.

8. NUTRITIONAL VALUES
CARBOHYDRATES
 Human milk carbohydrate is comprised
principally of lactose, with a small
proportion consisting of oligosaccharides.
 Oligosaccharides are important in the host
defense of the infant as their structures
mimic specific bacterial antigen receptors.

9. LIPIDS
 Represents approximately 50 % of
the calorie intake.
 Fatty acids in human milk consist of
a high proportion of long-chain fatty
acids: palmitic, oleic, and the
essential fatty acids: linoleic, and
linolenic.

10.  Approximately 70 % of the proteins in
human milk are in the soluble whey and 30
% insoluble casein.
 Whey is easily digested and is associated
with more rapid gastric emptying.
 The major human whey protein is alpha-
lactalbumin while the major bovine whey
protein is beta-lactoglobulin, which may
contribute to protein allergy and colic.
PROTEINS

11. • Human breast milk contains immunoglobulins,
antimicrobial enzymes. It also contains anti-
inflammatory and tolerance-promoting
compounds, such as I L 10.
• Exclusive breastfeeding for at least 3 to 4 months
of age is associated with a reduced risk of atopy
and lowered incidence of recurrent wheezing
during the first 2 years of life.
IMMUNOLOGIC PROPERTIES

12. BREAST FEEDING…
MAMMA!!

13. CMA affects 2-6 % of infants.
It results from an immunological reaction to
one or more milk proteins.
CMA may be immunoglobulin E (IgE) or non-
IgE mediated, the involvement of two systems
increases the probability of CMA.
ESPAGHAN Guidelines for CMPA

14. Cow’s Milk Allergy (CMA): Key
Concepts

15. Cow’s Milk
USDA Dairy Products: Per capita consumption, United States. http://www.ers.usda.gov/data-products/dairy-data.aspx #.U+QWEPtRbTo
ADVERSE REACTIONS
can occur with milk consumption
Food source for
9000 YEARS
Current US consumption:
195 L/PERSON/YEAR

16. Classification of Adverse Reactions to
Food
Adverse Reaction to Food
Enzymatic Pharmacologic Other
Nontoxic Toxic
Non-Immune–Mediated Reaction1,2
(Food Intolerance)
 Due to lack of
particular enzyme
 Due to
components of
the food
 Immediate
food allergy
 Oral allergy
 Food protein
enteropathies
 Eosinophilic
gastroenteropathies
IgE-mediated Non-IgE mediated
(eg, T cell–mediated)
Immune-Mediated Reaction1-3
(Food Allergy)
 Neurologic
IgE=immunoglobulin E.
1. Burks AW, et al. Pediatrics. 2011;128(5):955-965.
2. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920.
3. Spergel JM. Allergy Asthma Clin Immunol. 2006;2(2):78-85.

17. Impact of Food Allergies
 Direct medical costs to the US health care system
of $4.3 billion annually for childhood food allergies1
– Include clinician visits, emergency department visits, and
hospitalization
 Costs borne by the family of $20.5 billion annually for
childhood food allergies1
– Include lost labor productivity, out-of-pocket, and
opportunity costs (caregiver needing to leave or change
job)
 Quality of life decreased in UK, North American,
European, and Asian studies2-5
 Risk of compromised nutrition
 Long-term impact on feeding behaviors
 Risk of fatal reaction6
1. Gupta R, et al. JAMA Pediatr. 2013;167(11):1026-1031. 2. Avery NJ, et al. Pediatr Allergy Immunol. 2003;14(5):378-382. 3. Leung TF, et al. Clin Exp Allergy. 2009;539(6):890-896.
4. Flokstra-de Blok B, et al. Allergy. 2010;65(2):238-244. 5. Primeau MN, et al. Clin Exp Allergy. 2000;30(8):1135-1143. 6. Bock SA, et al. J Allergy Clin Immunol. 2001;107(1):191-193.

18. Family History and Physical
Examination During Early Diagnosis
Key observations helpful upfront1:
 Learn about personal and family history of allergic disease
 Identify and create a list of suspected foods
 Document the precise description of reactions
Key symptoms to watch for during a physical
examination1,2:
 Cutaneous: Flushing, hives, angioedema, and eczema
 Gastrointestinal: Oropharyngeal pruritus and edema, abdominal
cramping, nausea, vomiting, and diarrhea
 Pulmonary: Rhinorrhea, laryngeal edema, wheezing, coughing and
shortness of breath
 Cardiovascular: Hypotension, tachycardia, and arrhythmias
 Behavioral: Irritability (preceding or in combination with other
symptoms)
1. Sampson HA. J Allergy Clin Immunol. 1999;103(6):981-989. 2. Burks AW, et al. Pediatrics. 2011;128(5):955-965.

19. Important Gastrointestinal
Manifestations Associated With
Non-IgE–mediated Food Allergy
 Eosinophilic esophagitis, Gastroenteritis1,2:
– Postprandial vomiting, anorexia, abdominal distention, steatorrhea, failure to thrive,
weight loss, food impaction, and gastric outlet obstruction
– A subset with food-induced IgE-mediated reactions
 Dietary protein enteropathy2:
– Diarrhea, failure to thrive, abdominal distention, and malabsorption
– Less frequent anemia, edema, and hypoproteinemia
 Dietary protein enterocolitis2:
– Vomiting and diarrhea
 Dietary protein proctocolitis2:
– Gross blood in stool + other symptoms
 Celiac disease1:
– Diarrhea, steatorrhea, malabsorption, abdominal distention, flatulence, + nausea and
vomiting, failure to thrive, oral ulcers
– Associated skin disease: dermatitis herpetiformis
1. Spergel JM. Allergy Asthma Clin Immunol. 2006;2(2):78-85.
2. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920.

20. Description of Allergic Reactions:
 Key items to note during an early
diagnosis1,2:
– Timing of onset in relation to food ingestion
– Symptoms, their severity and duration of reaction
– Treatment of reaction
– Reproducibility of reaction after ingestion of suspected food
– Most recent reaction
1. Sampson HA. J Allergy Clin Immunol . 1999;103(6):981-989. 2. Sampson HA et al. J Allergy Clin Immunol. 2014;134(5):1016-1025.e40.

21.  Quick onset1-3
 Anaphylaxis, etc1-3
 Well-defined mechanism1
 Easier to diagnose1
 Validated tests1-3,a
 Delayed onset1-3
 Eczema, reflux, etc2
 Mechanism unclear2
 Harder to diagnose2
 No validated tests1,2
IgE-Mediated Versus Non-IgE–
Mediated Reactions
IgE
Non-IgE
aNot in infants.
1. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920.
2. Burks AW, et al. Pediatrics. 2011;128(5):955-965.
3. Wang J, Sampson HA. J Clin Invest. 2011;121(3):827-835.

22. Features of IgE-Mediated Allergy1-3
1. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920.
2. Burks AW, et al. Pediatrics. 2011;128(5):955-965.
3. Sicherer SH, et al. Pediatrics. 2012;129(1):193-197.
Quick onset
Reproducible
Specific
symptoms
Specific foods
Positive tests

23. Some Non-IgE–Mediated Reactions
 Eosinophilic
gastroenteropathies
 Food protein–induced
proctocolitis
 Food protein–induced
enteropathy
 Food protein–induced
enterocolitis
 Eczema
 Reflux,colic
 Constipation
1. Burks AW, et al. J Allergy Clin Immunol. 2012;129(4):906-920.
2. Burks AW, et al. Pediatrics. 2011;128(5):955-965.

26. Milk Allergy Lactose
Intolerance
Cause An allergic reaction to the protein
in milk and milk products
A negative reaction to
the sugar in milk and
milk products.
Symptoms •Persistent diarrhea
•Vomiting
•Skin Rashes
•Extreme fussiness
•Low or no weight gain
•Gassiness
•Wheezing
•Bloating
•Gassiness
•Diarrhea
Age of Onset •First few weeks or months of
life (usually not after age 2)
•Symptoms usually resolve at
age 3 or 4.
•Can develop at any
age, but usually not
in infants
•Usually does not
go away.
Treatment •If the infant is breastfed:
•Mothers should remove all
milk proteins from their diet.
•If the infant is bottle fed:
Switch to a hypoallergenic
amino acid-based formula .
•Avoid products
with lactose
•Some amount of
lactose may be
tolerated by most
persons.

27. What Factors May Help Explain
an Increase in Food Allergy
Prevalence?
 Changes in Diet1,2
– Vitamin D: An association between low Vitamin D levels and increased
risk of FA has been suggested1
– Antioxidants: Some data with asthma but none yet with FA1
– Obesity: Obesity is associated with an inflammatory state; mostly studied
in asthma1
– Dietary Fat: Despite the earlier results, recent meta-analysis found no
clear evidence to support the use of Omega 3 and Omega 6 fatty acids for
the primary prevention of atopic allergic disease development or
sensitization2
 Hygiene Hypothesis3
– Lack of exposure to infectious agents and gut
flora increases susceptibility to allergic
diseases; limited data for FA, except for mild
effect of cesarean delivery
FA=food allergy.
1. Sicherer SH et al. J Allergy Clin Immunol. 2014;133(2):291-307. 2. Anandan C et al. Allergy. 2009;64(6):840-848. 3. Kim H et al. Korean J Pediatr. 2013;56(9):369-376.

28. Hygiene Hypothesis

29. Symptoms of Cow’s Milk Protein Allergy
Can Mimic GERD in Infants
• Recent American Academy of Pediatrics
(AAP) guidelines for the management of
gastroesophageal reflux recognize that cow’s
milk protein allergy may have a clinical
presentation that mimics GERD in infants
AAP treatment algorithm (2013) for recurrent regurgitation and weight loss
Lightdale JR, et al. Pediatrics. 2013;131(5):e1684-e1695.
Algorithm used with permission of American Academy of Pediatrics.
Education
Close
follow-up12
Improved?11
No
Yes
Consider: Hospitalization:
Observe parent/child interaction
Consider: NG or NJ tube feedings
Consultation with Pediatric GI
Consider: Acid suppression
therapy and/or prokinetics
13
Education
Close
follow-up6
Evaluate
further
4
Adequate
calorie intake?5
Are
there warning
signs?
3
No
Yes
No
Yes
CBC, U/A, electrolytes, creatinine, urea,
celiac screen (> 6 months)
Consider: Upper GI series
7
History and physical examination2
Vomiting/regurgitation
and poor weight gain
1
Manage
accordingly
9
Abnormal?8
No
Yes
Dietary Management: Maternal exclusion diet in breastfed infants
(Protein/hydrolysate formula in formula-fed infants)
Thickened feedings
Increased caloric density
10
• Accordingly, AAP recommends the following
dietary modifications as a
first-line approach to reflux management:
– Exclusion of cow’s milk and eggs
from the diet of mothers who
breast-feed their infants
– Protein hydrolysate formula
in formula-fed infants
– Thickened feeding

30. DIAGNOSTIC
PROCEDURES

31. The first step is a thorough history and
physical examination.
 In most cases with suspected CMA, the
diagnosis needs to be confirmed or
excluded by an allergen elimination and
challenge procedure. ESPGHAN Guidelines , 2013

32.  Children with gastrointestinal manifestations of CMA
are more likely to have negative specific IgE test results
compared with patients with skin manifestations.
Specific IgG Antibodies or Determination of IgG
antibodies or IgG subclass antibodies against CMP has
no role in diagnosing CMPA & not recommended.
ESPGHAN Guidelines ,

33. Food Allergy Management
Current management
of food allergy includes
PHARMACOTHERAPY
(in case of accidental exposure
to the antigen)
STRICT ALLERGEN
AVOIDANCE
(exclusion diet)
Chapman JA, et al. Ann Allergy Asthma Immunol. 2006;96(suppl):S1-S68.

34. Milk for atopic babies

35. The Long-term Effect of Nutritional Intervention With Hydrolysate Infant
Formulas on Allergy in High-risk Children—The German Infant Nutrition
Intervention (GINI) Study
 GINI was a study of 2,252 infants at high risk for atopy, enrolled
at birth and followed through 10 years
 Infants randomized at birth to receive 1 of 4 formulas: an intact
cow’s milk formula or 1 of 3 hydrolyzed formulas: pHF-W, eHF-
W, eHF-C
 Strict intervention period as substitute for breast milk was
4 months to avoid modification of formula effect by solid foods
 Follow-up at 10 years with ISAAC questionnaire and invitation
to study center for examination and blood sampling
eHF-C=extensively hydrolyzed casein formula; eHF-W=extensively hydrolyzed whey formula; ISAAC=International Study of Asthma and Allergies in Childhood; pHF-W=partially hydrolyzed
whey formula.
von Berg A et al. J Allergy Clin Immunol. 2013;131(6):1565-1573.

36. The GINI Study—10 Year Analysis
 2 key takeaway points from the
GINI study:
– Feeding with the pHF-W and eHF-
C formulas in the first 4 months has
a positive effect on cumulative
incidence of atopic
eczema/dermatitis in high-risk
children, lasting until 10 years
– However, feeding cow’s milk
protein hydrolysate formulas
compared with cow’s milk formula
has neither a positive effect on
asthma and allergic rhinitis nor
such an effect
on allergic sensitization
Physiciandiagnosedeczema[adj.%]
Adjusted cumulative incidence of parent-reported
physician-diagnosed eczema
45
40
35
30
25
20
15
10
9
8
7
6
0
1 2 3 4 5 6 7 8 9 10
Age [years]
pHF-W
eHF-C
eHF-W
CMF
CMF=standard cow’s milk formula; eHF-C=extensively hydrolyzed casein formula; eHF-W=extensively hydrolyzed whey formula; pHF-W=partially hydrolyzed whey formula.
Reprinted from J Allergy Clin Immunol. 2013;131(6):1565-1573. Von Berg A et al. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year
results from the German Infant Nutritional Intervention (GINI) study. ©2013, with permission from Elsevier.
Overall Study Conclusion: These results support the use of cow’s milk protein hydrolysate infant formula in high-risk infants to reduce the
risk for atopic eczema but not for respiratory allergies

37. Babies at high risk for developing
allergy
First degree relatives with
either :
 Food allergy
 Asthma
 OR moderate to severe atopic
dermatitis (AD).

38.  Human milk is the optimal source
of nutrition for term infants during
the first 6 months of life.
 There is no evidence to support
administration of a hydrolyzed
formula, in preference to exclusive
breastfeeding, to prevent allergy.
AAP Website , 2015

39.  To prevent allergic diseases in high risk
infants, who cannot be exclusively
breastfed, a partially or extensively
hydrolyzed formula, in preference to a
conventional cow's milk or soy protein
formula can be offered.
AAP Website , 2015

40. Evaluation of an Amino Acid−Based
Formula in Infants Not Responding to
Extensively Hydrolyzed Protein Formula
J Pediatr Gastroenterol Nutr. 2016 Nov; 63(5): 531–
533.

41.  Recommended management of CMPA includes the initiation of
a hydrolyzed protein formula.
 Although 90% of infants exhibit healthy growth and reduced
allergic symptoms on an EH formula, highly sensitive infants
may require an AAF.
 Incidence and severity of AD and vomiting/spitting up were
significantly reduced during the 12-week study period ,
indicating that the AAF properly managed CMPA symptoms.

42.  In a prospective, controlled study, atopic infants
with CMPA receiving an AAF for 6 months
demonstrated clinical improvement and proper
growth compared with infants fed an EHP formula .
 In another study, data suggested that
hypoallergenic (AAFs) improved the gut barrier
function and minimized gastrointestinal
complications in atopic infants.
 The results in the study indicated that longer-term
feeding of an AAF in infants with poorly managed
CMPA, improved long-term allergy management.

43. KEY MESSAGES

44.  Allergy march is a worldwide problem!
 Be proactive in preventing allergic
diseases in infants and children rather than
treating a current condition.
 Breast milk is the gold standard for feeding
babies , either atopic or non atopic.

45.  There is no evidence to support administration of a
hydrolyzed formula, in preference to exclusive
breastfeeding, to prevent allergy.
 To prevent allergic diseases in high risk infants,
who cannot be exclusively breastfed, a partially or
extensively hydrolyzed formula, in preference to a
conventional cow's milk or soy protein formula.

46.  If the infant has milk protein allergy & breastfed,
mothers should remove all milk proteins from their
diet.
 If the infant is bottle fed, switch to a
hypoallergenic formula, either partially or
extensively hydrolyzed formula.
 However , some babies may need an amino acid
based formulas to improve allergic manifestations
& growth.