3. Learning Objectives
1. Apply current standard of care for the diagnosis and management of cow’s milk allergy in
infants
2. Distinguish between IgE mediated and non IgE mediated food reactions
3. Specify nutritional strategies to manage CMPA in infants
4. Case 1
A male preterm infant was born at 33 weeks gestation with a birthweight of 980 g
Treated for respiratory distress with conventional mechanical ventilation for 3 days.
Preterm formula was started on day 2.
On day 3, he developed feeding intolerance with bilious and bloody gastric residuals
The abdomen was distended with decreased bowel sound.
CRP (-), Occult blood (-), Blood and CSF cultures (-). An abdominal radiograph demonstrated
marked dilation of the stomach with normal bowel gas pattern.
The infant was treated as probable NEC, feeds were stopped for 3 days and he was given
empirical antibiotics for 7 days.
Enteral feeds were restarted with premature formula which resulted in recurrence of
increased gastric residuals and poor weight gain
5. Case 2
A boy delivered by NVD at term was exclusively breastfed till the age of 3 and a half months
He had normal weight gain and was doing well
His mother added regular infant first age formula to supplement her decreasing breast milk
One week later he developed a rash all over his trunk and was increasingly agitated, both
while feeding and during the night.
Diagnosed as eczema and given an emollient cream
But after 6 long weeks of treatment and repeated trips to the pediatrician, he wasn’t getting
any better.
He was feeding 6 times a day, passing loose stools, and waking up crying throughout the
night.
6. Case 3
A 25-day old boy was brought for consultation because he had fresh red blood in stools,
he was in no distress and was looking well
Breastfed exclusively
From birth the child had suffered from recurrent regurgitation but without any clinical
significance.
He was treated with positioning and frequent feeds with poor result
7. Case 4
A 2-month-old girl was rushed to ER because of incoercible vomiting, pallor and
lethargy of few hours' duration.
She had no fever but was pale with hypotonia, had a low blood pressure and tachycardia
Exclusively breastfed, she received supplemental infant formula, for the first time this
morning
Her sepsis work up was negative
Her serum IgE levels were normal
8. Key point 1
The clinical presentation of CMPA is variable
9. Introduction
Food allergy is defined as an adverse health effect arising from a specific immune
response that occurs reproducibly following exposure to a given food
The immune reaction may be IgE mediated, non-IgE mediated, or mixed
Cow’s-milk protein(CMP) is the leading cause of food allergy in infants and young
children younger than 3 years
Symptoms are nonspecific and easily confused with GERD, lactose intolerance or
functional GI disorders
Risk for over and under diagnosis and therefore over and under-treatment.
Boyce JA, et al. J Allergy Clin Immunol . 2010;126:S1 58; Nowak Wegrzyn A, et al. Nat Rev Gastroenterol Hepatol . 2017;14:
10. Guidelines
1. The European Society of Pediatric Gastroenterology, Hepatology and Nutrition
(ESPGHAN)
2. The European Academy of Allergy and Clinical Immunology (EAACI)
3. The Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA).
4. Three guidelines exist in the United Kingdom (UK) which include the National Institute
for Clinical Excellence Guidelines (NICE)
5. Two published guidelines specific for CMPA: one aimed at primary care (Milk Allergy in
Primary Care (MAP) guidelines) and the other for secondary and tertiary care,
published by the British Society for Allergy and Immunology
11. Knowledge and application of current guidelines on CMPA
Guideline Not aware Aware but not
read
Somewhat
familiar
Familiar but
not
following
Very
familiar and
following
NICE 18% 24% 45% 6% 7%
MAP 55% 23% 17% 3% 2%
ESPGHAN 81% 13% 4% 1% 0%
12. Epidemiology
True CMPA peaks in the first year of life, with a prevalence of approximately 2% to 3% in
the infant population .
This prevalence then falls to <1% in children 6 years of age and older.
A few exclusively breast-fed infants may also develop clinically significant CMPA via dairy
protein transfer into human breast milk
15. By Age
All Ages 0-17 years
Gupta R. et al. PEDIATRICS Volume 142, number 6,
December 2018:e20181235
16. Mislabeled cow’s milk allergy in infants:
a prospective cohort study
Arnon Elizur et al. Arch Dis Child 2013;98: 408–412.
Total Suspected
CMPA
381 100%
IgE-mediated 66 17.4%
Non IgE-mediated 72 18.9%
Mislabeled 243 63.7%
17. Time trends of childhood food allergy in China:
Three cross-sectional surveys in 1999, 2009, and 2019
The three studies included 1228 children (314 in 1999, 401 in 2009, and 513 in 2019)
The prevalence of FA was 3.5% in 1999, 7.7% in 2009 and 11.1% in 2019
There was evidence of increased prevalence in CMPA between 1999 and 2019 (1.6%
versus 5.7%; P = .004)
The incidence of skin symptoms did not differ significantly over the study period, while
the incidence of gastrointestinal symptoms increased significantly (18.2% in 1999, 12.9%
in 2009, and 43.9% in 2019; P < .05)
Zhuoying Ma et al. Pediatric Allergy and Immunology, Volume32, Issue5 July 2021 Pages 1073-1079
18. The Role Of Genetics In Predisposition To Food Allergy
A recent study of familial aggregation observed the heritability of common food
allergies (peanut, wheat, milk, egg white, soy, walnut, shrimp, and fish) to be between
0.15 and 0.35 suggesting genetic factors are not as important as other factors, such as
environmental exposures, in the development of food allergies.
Curr Opin Pediatr. 2009 December ; 21(6): 770–776. doi:10.1097/MOP.0b013e32833252dc.
19. Genetic Predisposition
Allergy risk in family 0 Parent
with Allergy
1 Parent with
Allergy
2 Parents with
Allergy
Percentage of
newborns
70% 25% 5%
Probability of later
allergies in their
children
15% 20 – 40% 50 – 80%
Curr Opin Pediatr. 2009 December ; 21(6): 770–776. doi:10.1097/MOP.0b013e32833252dc.
20. Family history of atopy in infants with cow's milk protein allergy:
A French population-based study
N.Kalach et al. Archives de Pédiatrie, Volume 26, Issue 4, May 2019, Pages 226-231
21. Family history of atopy in infants with cow's milk protein allergy:
A French population-based study
N.Kalach et al. Archives de Pédiatrie, Volume 26, Issue 4, May 2019, Pages 226-231
22.
23.
24.
25.
26.
27. Differences between IgE- and non-IgE-mediated cow’s milk allergy
IgE mediated
1. Immediate within minutes
2. Dose independent
3. Likely to have measurable IgE
4. Anaphylaxis
5. Urticaria, angioedema
6. Acute Diarrhea, vomiting
7. Acute asthma
8. No rectal bleeding
Non IgE mediated
1. Variable prolonged time from exposure
2. Dose dependent
3. Not likely to have measurable IgE
4. Predominant GI smpx
5. Chronic rhinorrhea
6. Chronic eczema
7. Resistant GERD
8. Blood in stools
9. Never anaphylaxis
Lifschitz C, et al. Eur J Pediatr . 2015;174:141 50.
28. Key point 2
IgE- mediated reactions are immediate, non IgE-mediated are delayed
29. Cow’s milk protein allergy
A multi-center study: clinical and epidemiological aspects
Martorell A. et al. Allergol et Immunopathol 2006;34(2):46-53
• Patients diagnosed with CMP allergy
Percentage distribution in relation to the
age when the first reaction to CMP took
place.
• 95.5% would manifest their first
symptoms before 6 months of age
30. Key point 3
The majority of CMPA present in the first 6 months
31. Clinical presentation
Immediate (early, minutes up to 2 hours) more likely IgE
Delayed (late, >72 hours) more likely non-IgE
May involve different organ systems (Skin, GI, Respiratory)
Clinically difficult to differentiate between IgE and Non-IgE
Anaphylaxis, Angioedema, and Atopic eczema IgE
Severe shock-like reactions with metabolic acidosis are characteristic for the
‘‘food protein–induced enterocolitis syndrome,’’ which is a non–IgE-mediated
manifestation
32. GI signs & symptoms
Due to inflammation, dysmotility, malabsorption or a combination of all
Dysphagia, vomiting and regurgitation
Anorexia and food refusal
Diarrhea with or without malabsorption
Rectal bleeding
Failure to thrive
33. Clinical features of cow's milk protein allergy in infants presenting
mainly with gastrointestinal symptoms: an analysis of 280 cases
A retrospective analysis was performed for the clinical data of 280 hospitalized infants,
who were diagnosed with CMPA presenting mainly with gastrointestinal symptoms.
Among the 280 infants, 203 infants(72.5%) were aged of less than 6 months.
The breastfeeding CMPA group had significantly lower incidence rates of malnutrition
Yang, Qing-Hua Journal:Zhongguo dang dai er ke za zhi ISSN:1008-8830; 2019 Volume: 21 Issue: 3 Page: 271-276
34. Diarrhea 61.1%
Hematochezia 53.2%
Vomiting 25.4%
Eczema 20.4%
Malnutrition 15%
Constipation 4.6%
Yang, Qing-Hua Journal:Zhongguo dang dai er ke za zhi ISSN:1008-8830; 2019 Volume: 21 Issue: 3 Page: 271-276
35. Mild/ Moderate CMPA 92.1%
Severe CMPA 7.1%
Total 280
Yang, Qing-Hua Journal:Zhongguo dang dai er ke za zhi ISSN:1008-8830; 2019 Volume: 21 Issue: 3 Page: 271-276
37. Symptoms in 182 patients less than one year of age with
confirmed CMPA
Min Yang et al. Journal of Parenteral and Enteral Nutrition Volume 0 Number 0 xxx 2018 1–6
38. Symptoms in 182 patients less than one year of age with
confirmed CMPA
Min Yang et al. Journal of Parenteral and Enteral Nutrition Volume 0 Number 0 xxx 2018 1–6
40. Non-IgE mediated CMPA
1. CMP-induced proctocolitis:
* The most common non-IgE
* Infancy, 2 months of age, occurs in the large bowel
* Healthy baby with colic and fresh blood in the stools
* More common in breast-fed babies (maternal dietary allergens)
* Diagnosis made by an elimination diet (mother and baby)
* Bleeding resolves in 72 hours
* SPT and serum IgE are negative
* Resolution by 12 months of age, sooner than IgE-mediated CMPA
41. Non-IgE mediated CMPA (2)
2. Food Protein-induced enteropathy:
* Protracted diarrhea with vomiting few weeks after the introduction of cow’s milk
* Results in lack of appetite, malabsorption, iron deficiency and stunted growth
* Presenting in infancy and resolving by 1-2 years of age
* SPT and serum IgE are negative
* Biopsy reveals mucosal inflammation and distortion of the villous architecture
* Difficult to differentiate from untreated Celiac disease
Calvani M. et al, Nutrients 2021, 13, 226. https://doi.org/10.3390/nu13010226
SPT: Skin Prick Test
42. Non-IgE mediated CMPA (3)
3. Food protein-induced enterocolitis syndrome (FPIES):
* An acute cell-mediated food hypersensitivity
* Acute diarrhea and vomiting, pallor and hypotonia following ingestion of cow’s milk
* Hypovolemic shock in 20%
* Symptoms appear between 1-3 hours after ingestion
* SPT and serum IgE are negative
* Absence of fever, presence of eosinophilic debris in the stools and negative stool cultures can
help differentiate these conditions
* After 2 years 60% can tolerate milk
43. Non-IgE mediated CMPA (4)
5. Heiner syndrome - Food Protein-Induced Pulmonary Hemosiderosis:
Also known as cow milk induced pulmonary disease is a rare disease resulting in atypical
lung disease in infants and young children.
It is characterized by recurrent respiratory tract symptoms, infiltrates mimicking
pneumonia on chest radiograph, fever, anemia and failure to thrive
These clinical features resolve within one to three weeks of discontinuation of cow milk
Sigua JA, Zacharisen M. Heiner syndrome mimicking an immune deficiency. WMJ. 2013;112(5):215–217.
44. Mixed CMPA (5)
4. Allergic eosinophilic gastroenteropathies:
* Eosinophilic esophagitis, gastroenteritis and enterocolitis
* Food refusal, faltering growth
* Mechanism unknown
* Exclusion diet is rarely enough to control symptoms, and antihistamine, steroids and
leukotriene receptor antagonists might be required
45. Diagnostic procedures
Hx and PE
Serum Specific IgE
Skin Prick Test (SPT)
Oral Challenge Test (OCT, open, single- or double-blind)
46. The allergy-focused clinical history
1. Any family history of atopic disease in parents or siblings.
2. Any history of early atopic disease in the infant.
3. The infant’s feeding history including growth.
4. Presenting symptoms and signs that may be indicating possible CMA.
5. Details of previous management, including any medication and the perceived response
to any treatment or dietary change.
Adapted from the UK NICE guideline CG116 on food allergy
49. Skin Prick Test (SPT)
Advantages Disadvantages
Easy to perform
Non-invasive
Immediate results
Cost effective
Negative test is highly predictive
of absence of allergy
Parents can “see” result
Must stop antihistamines 48 h
before testing
Severe eczema or dermographism
may prevent use
Not all substances available
50. The predictive value of skin prick testing for challenge-proven
food allergy: A systematic review
Skin prick tests (SPTs) can detect the presence of allergen-specific IgE antibodies
(sensitization)
SPT thresholds with a high probability of food allergy generated from these studies may
not be generalizable to other populations, because of highly selective samples and
variability in participant’s age, test allergens, and food challenge protocol.
Standardization of SPT devices and allergens, OFC protocols including standardized
cessation criteria, and population-based samples would all help to improve
generalizability of PPVs of SPTs.
Rachel L. et al. 04 December 2011 https://doi.org/10.1111/j.1399-3038.2011.01237.x
51. Specific IgE tests
Advantages Disadvantages
No need to stop antihistamines
Appropriate when standardized skin
prick testing not available
Can be used in patients with skin
disorders e.g., eczema, urticaria
Expensive
Invasive
Delay in obtaining results
*May be misleading if total IgE level is
very high*
52. Food-specific serum immunoglobulin E measurements in
children presenting with food allergy
A parallel observational study, including 820 infants and children under 2 years of age
(median age of 13.1 months) with suspected allergy to cow's milk, eggs, or peanuts,
compared the diagnostic agreement between food-specific IgE antibody levels and SPT.
When applying published 95% positive predictive specific IgE values, the diagnostic
accuracy of SPT and IgE antibody levels was similar for cow's milk, but SPT was more
sensitive in diagnosing allergy to egg ( P < .0001) and peanut ( P < .0001).
Ann Allergy Asthma Immunol. 2014 Feb;112(2):121-5. doi: 10.1016/j.anai.2013.09.027.
53. Differences among food-specific IgE diagnostic tests
David R. Stukus et al. Pearls and Pitfalls in Diagnosing IgE-Mediated Food Allergy Curr Allergy Asthma Rep (2016) 16: 34
54. Oral Challenge Test
Progressive introduction of CMP
1. Regimen A – first day: 2 ml, 5 ml,10 ml; second day: 25 ml, 50 ml; third day: 100 ml and the last dose to complete the
quantity equivalent to one normal feed were given at 60-minute intervals.
2. Regimen B – in a single day, successive doses of 2 ml, 5ml, 10 ml, 25 ml, 50 ml, 100 ml, were given at 30-minute
intervals.
If a clinical reaction appeared, the challenge was discontinued, and treatment was provided if
necessary.
The challenge was considered to be positive when there were skin (urticaria, angioedema, or
erythematous rash), gastrointestinal (vomiting or diarrhea), respiratory (rhino-conjunctivitis or
bronchospasms), or generalized (anaphylactic shock) manifestations in the 2 hours after the
intake of the food.
Martorell A, et al.—COW’S MILK ALLERGY. CLINICAL AND EPIDEMIOLOGICAL ASPECTS
55. Oral Challenge Test
The challenge test was considered contraindicated in cases of anaphylactic shock and/or
glottal edema and non-indicated in patients who met all the following criteria:
1. Urticaria and/or Angioedema.
2. Appearance of symptoms in the first 60 minutes after intake.
3. Positive skin tests (≥ 3mm) and specific IgE ≥3 kU/l to any of the proteins.
4. Less than 3 months since the last clinical reaction.
If the infant was still being breast fed, the challenge test was postponed until the start of
artificial lactation.
Martorell A, et al.—COW’S MILK ALLERGY. CLINICAL AND EPIDEMIOLOGICAL ASPECTS
56. • 20 patients underwent accurate clinical examination and laboratory test investigations
(total blood cell count, aminotransferase, total Ig E levels, Specific IgE levels,
Betalactotest, prick tests with fresh milk, chemical examination of the stools, fecal
eosinophilic cell count).
• Skin Prick Test (SPT) and RAST were positive in one patient (1/20). Laboratory tests were
negative in all others.
• DBCT was carried out in all 20 patients
PITFALLS IN DIAGNOSIS OF CMPA
Accomando S. et al, Digestive and Liver Disease2011 Vol. 43; Iss. supp-S5
57. • Results: The challenge was positive only in one patient with negative SPT and IgE
• Conclusions:
1. A diagnostic test for CMPA does not exist, so elimination diets and DBCT are the gold
standards for the diagnosis.
2. The data show that DBCT disprove many CMPA diagnosis and therefore, many
unjustified elimination diets which may lead to severe impairment in growth with
secondary failure to thrive.
3. Gastrointestinal and dermatological signs represent the major pitfalls for pediatricians,
inducing frequently a false diagnosis of CMPA.
4. Finally, laboratory tests aren’t predictors for DBCT response.
PITFALLS IN DIAGNOSIS OF CMPA
Accomando S. et al, Digestive and Liver Disease2011 Vol. 43; Iss. supp-S5
58. Key point 4
Elimination diet and Oral Challenge Tests are the gold standards for the
diagnosis of CMPA
59. Evolution
Most cases of cow’s milk allergy resolve by the age of 3 years, with resolution in
1. 56% at 1 year
2. 77% at 2 years
3. 87% at 3 years
4. 92% at 5 and 10 years
5. 97% at 15 years of age.
Justin M. Skripak; J Allergy Clin Immunol 2007;120:1172-7
60. The Natural History of Non-IgE Mediated
Cow's Milk Allergy
Retrospective chart review of 34 pediatric patients with non-IgE mediated CMA in a
tertiary referral clinic
The median age at first evaluation was 1 year (range: 0-14years) and the median
duration of follow-up was 2 years (range: 0-16years).
The age at onset of CMA symptoms was <6 months in 91% (range: 0-10 years).
Presenting symptoms included reflux/vomiting 73%, bloody stools 47%, colic/pain 41%,
diarrhea 24%, and food refusal/failure to thrive 15%.
Milk tolerance was documented in 50% (n=17) by the end of follow-up.
S. K. Driggers et al. https://doi.org/10.1016/j.jaci.2008.12.217
61. Prospective follow-up oral food challenge in food
protein-induced enterocolitis syndrome
Non–IgE mediated food allergy to cow’s milk resolves sooner than the IgE mediated
form.
Most children grow out of non–IgE mediated disease by 1 year of age.
In a prospective study, resolution of cow’s milk and soy infantile food protein
enterocolitis syndrome occurred in 27.3% and 75.0% at 6 months of age, 41.7% and
90.9% at 8 months, and 63.6% and 91.7% at 10 months, respectively.
Arch Dis Child. 2009 Jun;94(6):425-8.
62. Long-term Outcomes of Children with Cow’s Milk Protein
Allergy in a Pediatric Allergy Clinic
Aim: This study aimed to assess the clinical features, management, and long-term
outcomes of pediatric patients with cow’s milk protein allergy (CMPA).
Materials and Methods: Retrospective study consisting of 246 children with CMPA.
Results: During five years of the follow-up period, tolerance occurred in 78.9% of the
patients.
Conclusion:
1. The prognosis of the disease was favorable with a spontaneous tolerance developed by
the age of three in most patients.
2. IgE-mediated hypersensitivity reactions, a family history of atopy and higher specific IgE
values were predictive factors for the long-lasting disease.
JOURNAL OF PEDIATRIC RESEARCH (SEP 2021) https://doi.org/10.4274/jpr.galenos.2020.24572
63. Incidence and natural history of challenge-proven cow’s milk
allergy in European children–EuroPrevall birth cohort
100% of patients with non-IgE mediated CMA developed tolerance within 1 year
57% of those with IgE-mediated CMA developed tolerance within 1 year
Schoemaker, A.A et al.. Allergy 2015, 70, 963–972.
65. • Always reintroduce milk from stage 1, do
not proceed to the next stage if any slight
reaction occurs (e.g., milk rashes, tummy
ache)
• Try a small amount the first day and then a
larger portion the following day.
• If tolerated, gradually increase to a normal
portion appropriate for the child’s age.
The Milk ladder
66. Potential Protein Breakdown Hydrolytic Stages of an
Antigenicity antigenic protein molecule
High Intact protein
Large peptides
Small peptides
Low Amino acids
eHF, pHF and Amino-acid Formulas
67.
68.
69. 1. Anaphylaxis
2. Eosinophilic esophagitis
3. Heiner’s Syndrome
4. Failure to thrive
5. Food protein induced enteropathy syndrome (FPIES)
6. Severe eczema (hypoalbuminemia, failure to thrive)
Koletzko et al. ESPGHAN Guideline: Diagnosis and Management of CMPA. JPGN2012;55: 221–229
When to use AAF as first line?
70. Proteins Quantity
(grams/100 ml)
Lactose Calories MCT
Allernova Casein 1.6 eHF no 66.8 35%
Aptamil PJ Whey 1.8 eHF yes 68
Nutramigen Casein 1.9 eHF no 68
Friso Pep
AC
Casein 1.6 eHF no 66.8
EleCare A-A 2.09 A-A no 67.56 33%
Neocate A-A 1.9 A-A no 70 35%
72. Key point 6
There’s no place for partial hydrolysates in the management of CMPA
No Soy milk before 6 months
73. Allergenicity and use in treatment and prevention
It has been shown that small amounts of cow’s milk proteins and other foods such as
egg and peanut, can reach the infant via breast feeding
The quantity of beta-lactoglobulin contained in a drop of cow’s milk correspond to the
quantity of beta-lactoglobulin in 200 liters of mother’s milk.
But even so, mother’s milk contains approximately as much beta-lactoglobulin per drop
as the amount of pollen allergen inhaled per day during the hay fever season.
Therefore, it is possible for children to become sensitized to cow’s milk, even though
they are breast fed exclusively
Businco L, et al. Pediatr Allergy Immunol. 1993;4:101-11.
74. Induction of systemic immunologic tolerance to
beta-lactoglobulin by oral administration
of a whey protein hydrolysate
The main advantage of breast feeding in the prevention of food sensitization is based
fundamentally on the relative lack of food allergens in human milk.
However, this is a double-edged weapon, as experimental studies in animals indicate
that:
Small quantities of antigen, at microgram to picogram level, can preferentially induce
IgE responses
Larger quantities, at the milligram level, suppress the IgE response and the degree of
suppression depends on the dose.
Fritsche R, Pahud JJ, Pecquet S, Pfeifer A.. J Allergy Clin Immunol. 1997;100:266-73.
75. Milk feeding of infants and
cow’s milk protein hypersensitivity
Clinical experience indicates that, in those infants receiving artificial adapted cow’s milk
formula from birth, the appearance of CMP allergy is exceptional.
Only two of the 234 infants diagnosed with CMP allergy had received artificial milk from
birth.
In these two cases, the administration of the adapted formula had been interrupted at one
month of age due to digestive symptoms, with its being substituted by an extensive
hydrolysate, with an allergic reaction to CMP occurring when adapted cow’s milk formula
was reintroduced.
Ghisolfi J, Olives JP, Le Tallec C, Cohen J, Ser N.. Arch Pediatr. 1995;2:526-31.
76. Early Discontinuation of Cow's Milk Protein Ingestion Is
Associated with the Development of Cow's Milk Allergy
METHODS: They compared the proportions of participants who developed CMA at age 6
months in those who ingested CMF in the first 3 days of life and discontinued CMF before
age 1 month, during age 1 to 2 months, and during age 3 to 5 months with those who
continued CMF ingestion until age 6 months.
RESULTS: CMA incidence was significantly higher in the discontinuous <1-month group
(41.2%) 1-2-month group (11.5%), and 3-5-month group (10.1%) than in the continuous
group (0.6%).
CONCLUSIONS: Early CMF discontinuation, particularly in the first month of life, was
associated with CMA development in infants who received CMF in the first 3 days of life.
Sakihara et al. The journal of allergy and clinical immunology in practice. DOI:10.1016/j.jaip.2021.07.053
77. Randomized trial of early infant formula introduction
to prevent cow’s milk allergy
The study sample comprised 491 participants (242 in the ingestion group and 249 in the
avoidance group)
Participants were randomly allocated to ingest at least 10 mL of CMF daily (ingestion
group) or avoid CMF (avoidance group) between 1 and 2 months of age.
In the avoidance group breast-feeding was supplemented with soy formula as needed.
Oral food challenge was performed at 6 months of age to assess CMA development.
Continuous breast-feeding was recommended for both groups until 6 months of age.
There were 2 CMA cases (0.8%) among the ingestion group and 17 CMA cases (6.8%)
among the avoidance group.
Daily ingestion of CMF between 1 and 2 months of age prevents CMA development.
Sakihara, Tetsuhiro et al. Journal of allergy and clinical immunology, 01/2021, Volume 147, Issue 1
78. Milk related excipients in drug products
Analyzed
medicines
With milk related
excipients
Ibuprofen (oral suspensions, pediatric suppositories and 400 mg tablets) 38 12
Paracetamol (syrups, pediatric suppositories and 1 g tablets) 27 1
Iron compounds (non-injectable formulations) 12 3
Bacteria/yeast to replace intestinal flora 6 6
Amoxicillin (powder for oral suspensions) 11 0
Total 94 21
A. Figueiredo, M. Couto & I. M. Costa (2021) Milk related excipients in medications: concerns with cow’s milk protein allergy, Annals of Medicine, 53:sup1, S108-S108,
DOI: 10.1080/07853890.2021.1896091
79. Milk related excipients in drug products
Analyzed
medicines
With milk related
excipients
Ibuprofen (oral suspensions, pediatric suppositories and 400 mg tablets) 38 12
Paracetamol (syrups, pediatric suppositories and 1 g tablets) 27 1
Iron compounds (non-injectable formulations) 12 3
Bacteria/yeast to replace intestinal flora 6 6
Amoxicillin (powder for oral suspensions) 11 0
Total 94 21
A. Figueiredo, M. Couto & I. M. Costa (2021) Milk related excipients in medications: concerns with cow’s milk protein allergy, Annals of Medicine, 53:sup1, S108-S108,
DOI: 10.1080/07853890.2021.1896091
Conclusions: Several medicines contain lactose, but this excipient can be contaminated with milk proteins and may
trigger allergic reactions in CMPA patients.
80. Effect of Lactobacillus GG on tolerance acquisition in
infants with cow’s milk allergy: A randomized trial
Berni Canani et al, Journal of allergy and clinical immunology 2011 Volume: 129 Issue: 2 Page: 580-582.e5
5
1
17
8
0
2
4
6
8
10
12
14
16
18
eHF + LGG eHF
Number of patients acquiring tolerance
IgE-mediated Non IgE-mediated
Number of patients acquiring tolerance
eHF+LGG non-IgE
eHF IgE
eHF non-IgE
eHF+LGG IgE
81. 12
5
2
0
9
2
0
2
4
6
8
10
12
14
eHF+ LGG eHF -LGG Breast Milk
OBS (-) OBS (+)
Lactobacillus GG Improves
Recovery in Infants with Blood
in the Stools and Presumptive
Allergic Colitis Compared with
Extensively Hydrolyzed
Formula Alone
Baldassare et al. J Pediatr 2010;156:397-401
OBS: Occult blood in stools
Occult blood stool after 4 weeks of diet in patients with
s-CMAC with respect to the type of milk feeding
84. Suspected or Diagnosed CMPA
Eliminate Cow’s milk protein
Exclusively
Breastfed
Continue
Breastfeeding
Yes
Improvement
No Maternal CMP
elimination (4 wk)
Improvement
Continue until 1
year of age
CMP
reintroduction
Resolution of
symptoms
No
Yes
Continue with
elimination of CMP
Yes
85. Suspected or Diagnosed CMPA
Eliminate Cow’s milk protein
Exclusively
Breastfed
Continue
Breastfeeding
Yes
Improvement
No Maternal CMP
elimination (4 wk)
Improvement
Continue until 1
year of age
CMP
reintroduction
Resolution of
symptoms
No
Yes
AAF
4 weeks
Improvement
No
Standard CMF
Consider other
Allergies
No
Continue with
elimination of CMP
Yes
86. Suspected or Diagnosed CMPA
Eliminate Cow’s milk protein
Exclusively
Breastfed
No Anaphylaxis / Eosinophilic
esophagitis / Growth failure
Yes
AAF
4 weeks
Improvement
No
Standard CMF
Consider other
Allergies
Resolution of
symptoms
Continue with
elimination of CMP
Continue until 1
year of age
CMP
reintroduction
No
Yes
Yes
87. Suspected or Diagnosed CMPA
Eliminate Cow’s milk protein
Exclusively
Breastfed
No Anaphylaxis / Eosinophilic
esophagitis / Growth failure
Yes
AAF
4 weeks
Improvement
No
Standard CMF
Consider other
Allergies
No
Continue until 1
year of age
Resolution of
symptoms
Continue with
elimination of CMP
eHF
4 weeks
Improvement
Continue until 1
year of age
CMP
reintroduction
No
Yes
No Yes
88. Suspected or Diagnosed CMPA
Eliminate Cow’s milk protein
Exclusively
Breastfed
No Anaphylaxis / Eosinophilic
esophagitis / Growth failure
Yes
AAF
4 weeks
Improvement
No
Standard CMF
Consider other
Allergies
No
Age ≥6 months
If without Soy allergy
Soy formula for 4 weeks
Yes
Improvement
Continue until 1
year of age
Resolution of
symptoms
Continue with
elimination of CMP
No
eHF
4 weeks
Improvement
Continue until 1
year of age
CMP
reintroduction
No
Yes
No
No
89. Suspected or Diagnosed CMPA
Eliminate Cow’s milk protein
Exclusively
Breastfed
Continue
Breastfeeding
Yes
No
Improvement
No Maternal CMP
elimination (4 wk)
Improvement
Continue until 1
year of age
CMP
reintroduction
Resolution of
symptoms
No
Yes
Anaphylaxis / Eosinophilic
esophagitis / Growth failure
Yes
AAF
4 weeks
Improvement
No
Standard CMF
Consider other
Allergies
No
Continue with
elimination of CMP
No
Age 6 months
If without Soy allergy
Soy formula for 4 weeks
Yes
Improvement
Continue until 1
year of age
Resolution of
symptoms
Continue with
elimination of CMP
No
eHF
4 weeks
Improvement
Continue until 1
year of age
CMP
reintroduction
No
Yes
Yes
No
90. Take home message
1. CMPA is a disease of infancy
2. Low prevalence but difficult to diagnose
3. Under- or over-diagnosis may lead to under- or over-treatment
4. Symptoms similar to GERD, lactose intolerance or functional GI tract
disorders.
5. High suspicion if 2 or more systems involved
6. Two predominant pathophysiological mechanisms (IgE and non-IgE
mediated)
7. OCT after an eviction period remains the gold standard of diagnosis.
