What’s New in the Diagnosis and Management of Cow’s Milk Protein Allergy. Distinguish IgE and non-IgE mediated aspects of cow’s milk allergy (CMA). Review the clinical effects of formula in infants with CMA

2. ‫اآلية‬ ‫البقرة‬ ‫سورة‬32

3. COW MILK
PROTEIN
ALLERGY
Professor Khaled Saad,
MD, MSc, PhD

4. Cow milk
Protein
allergy

5. Agenda
• What’s New in the Diagnosis
and Management of Cow’s
Milk Protein Allergy.
• Distinguish IgE and non-IgE
mediated aspects of cow’s
milk allergy (CMA).
• Review the clinical effects of
formula in infants with CMA

6. Case 1
Vital Stats
Girl
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 per-
centile
Weight
3rd per-
centile
Case 2
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. Background

9. BREAST MILK
• Human breast milk contains IGs, antimicrobial
enzymes. It also contains anti-inflammatory and
tolerance-promoting compounds, such as IL-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.

10. BREAST FEEDING… MAMA!!

11. CMA is the most common food allergy of
young children, affecting 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

12. Cow’s Milk Allergy
(CMA): Key Concepts
*The use of cow’s milk
as a beverage probably
began around 9000
years ago with the
domestication of cattle.
*US consumption is
around 88 liter/
person/year.
*As milk consumption
increases, especially
among infants, there is
greater scope for
adverse reactions.
This may include behaviors such as:

13. Classification of
Adverse Reactions to
Food

14. 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
(e.g., 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.

15. Impact of
Food
Allergies
• Direct medical costs to the US health care
system of $4.3 billion annually for
childhood food allergies include clinician
visits, emergency department visits, and
hospitalization.
• Costs borne by the family of $20.5 billion
annually for childhood food allergies.
• Quality of life decreased in UK, North
American, European, and Asian studies.
• Risk of compromised nutrition.
• Long-term impact on feeding behaviors
and risk of fatal reaction.

16. Family History
and Physical
Examination
During Early
Diagnosis
Key observations for diagnosis:
•Learn about personal and family
history of allergic disease.
•Identify and create a list of
suspected foods.
•Document the precise
description of reactions.

17. Family History
and Physical
Examination
During Early
Diagnosis
Key symptoms to watch for during a physical
examination:
• Cutaneous: Flushing, angioedema, and
eczema
• GIT: 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)

19. Gastrointestinal Manifestations Associated With Non-IgE–
mediated Food Allergy
1. Eosinophilic esophagitis, GE 1,2:
• Postprandial vomiting, anorexia,
abdominal distention, steatorrhea,
failure to thrive, weight loss, food
impaction, and gastric outlet
obstruction
2. Dietary protein enteropathy2:
• Diarrhea, failure to thrive,
abdominal distention, and
malabsorption, less frequent
anemia, edema, and
hypoproteinemia
3. Dietary protein enterocolitis2:
• Vomiting and diarrhea
4. Dietary protein proctocolitis2:
• Gross blood in stool + other
symptoms
5. Celiac disease1:
• Diarrhea, steatorrhea,
malabsorption, abdominal
distention, flatulence, + nausea and
vomiting, failure to thrive, oral
ulcers, 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.
Reappearance of reactions 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
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.
IgE-Mediated Versus Non-IgE–Mediated Reactions

22. 1. Burks AW, et al. Pediatrics. 2011;128(5):955-965.
2. Sicherer SH, et al. Pediatrics. 2012;129(1):193-197.
Quick onset: 20 minutes (but up to 2 hours) after food ingestion
Reproducible
Specific symptoms: urticaria, angioedema, rhinorrhoea, diarrhoea,
vomiting
Specific foods
Positive tests
Features of IgE-Mediated Allergy

23.  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.
Some Non-IgE–Mediated Reactions

24. Differential
diagnosis

25. •Most commercially
available cow's milk
contains two types of beta-
casein: A1 and A2 types.
Digestion of A1 type yield
the peptide beta-
casomorphin-7, which has
been implicated in adverse
gastrointestinal effects of
milk consumption, similar
to those in lactose
intolerance

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. COMISS
score

28. COMISS
Score
Algorithm

29. What Factors May Help Explain an Increase in Food
Allergy Prevalence?
Changes in Diet
• Vitamin D: An association between low Vitamin D levels and
increased risk of food allergy.
• Obesity: Obesity is associated with an inflammatory state; mostly
studied in asthma
• 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 sensitization
Hygiene Hypothesis: 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

30. Hygiene Hypothesis

31. 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

32. DIAGNOSTIC
PROCEDURES

33. •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.
DIAGNOSTIC
PROCEDURES

34. DIAGNOSTIC
PROCEDURES
 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.

35. 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.

36. Milk for
atopic
babies

37. 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.

38. 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

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

40. MANAGEMENT

41. What is the key to CMPA ?
Feeding
Treatment
Prevention

42. 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.
Clinical
Practice
Treatment

43. • 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.

44. •To prevent allergic diseases in high risk
infants, who cannot be exclusively breastfed,
an extensively hydrolyzed formula, in
preference to a conventional cow's milk or
soy protein formula can be offered.

45. • Those breastfeeding infants who develop
symptoms of food allergy may benefit from:
a) maternal restriction of cow’s milk, egg,
fish, peanuts and tree nuts and if this is
unsuccessful,
b) use of a hypoallergenic (extensively
hydrolyzed or if allergic symptoms persist,
a free amino acid-based formula) as an
alternative to breastfeeding.
Clinical
Practice
Treatment

46. Those infants with IgE-associated
symptoms of allergy may benefit from a soy
formula, either as the initial treatment or
instituted after 6 months of age after the use
of a hypoallergenic formula. Concomitant
allergy to soy and cow’s milk in these
infants is lower compared with those with
non–IgE-associated syndromes such as
enterocolitis, proctocolitis, malabsorption
syndrome, or esophagitis. Benefits should
be seen within 2 to 4 weeks and the formula
continued until the infant is 1 year of age or
older.
Clinical
Practice
Treatment

47. Hydrolysed Formulas
ALLERGENICITY
Intact protein Partial hydrolysis Extensive
hydrolysis
Aminoacids
TOLERANCE
COST
Palatability

48. MW ALLERNOVA CMA/ Nutramigen
<1000 Da 82% 70%
1000-<2000 Da 15.6% 15%
2000-5000 Da 2.4% 15%
COMPARISON OF EHF (EXTENSIVELY HYDROLYZED FORMULA)

49. Allernova: Double Mode of
Action

50. Evaluation of an Amino Acid−Based
Formula in Infants Not Responding
to Extensively Hydrolyzed Protein
Formula
J Pediatr Gastroenterol Nutr

51. Recommended management of CMPA includes the
initiation of an extensive HF.
 Although 90% of infants exhibit healthy growth and
reduced allergic symptoms on an EHF, 10% of infants
with CMPA still react to the residual allergens in EHF.
ESPGHAN guidelines indicate that the risk to react to
EHF may be higher in the presence of severe
enteropathy or with multiple food allergies. For that
reason, AAF is considered as first-line treatment in
infants who fail to thrive, suffer from macronutrients
deficiencies and other life-threatening symptoms.

52. 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
EHF.
 In another study, data suggested that AAFs
improved the gut barrier function and
minimized GIT complications in atopic infants
and improved long-term allergy management.

53. AMINOVA
is the first
thickened AAF
for the dietary
management of
Severe CMPA
& Allergy to
EHF
100%
Free amino-
acid
Lactose Free
Macronutrients,
vitamins &
minerals
Unique
Thickening
Agent

54. Safety of a
New Amino Acid
Formula in
Infants Allergic
to Cow's Milk
and Intolerant to
Hydrolysates
The 1st HEAD TO HEAD RCT study
comparing Aminova and Neocate in
the management of severe CMPA
(Dupont et. al) (JPGN 2015;61: 456–463)

55. Proven Efficiency

56. GERD

58. Taste acceptance

59. Parents satisfaction

60. Side effects of old AAF: Hypophastatemia
Aktar et. al. 2019
Rickets/ fractures in 94% with High alkaline
Phosphatase, low phosphate. Corrected with
a change in phosphate supplement
Creo et. al. 2018
Rickets/fractures after median (range) of
8mo. (3-15mo.) High alkaline Phosphatase,
low phosphate. Corrected with phosphate
supplement

61. Side effects of old AAF: Hypophastatemia
Uday et. al. 2019
Children either on neocate, elecare, Showed
Rickets/fractures in 23% with High alkaline
Phosphatase, low phosphate. Corrected with
a change in formula/phosphate supplement.
These problems solved in new AAF
Aminova with adjusted Ca++ to
Phosphate ratio.

64. THANK YOU