dr. Komang Ayu Witarini, Sp.A(K)

dr. Komang Ayu Witarini, Sp.A(K)

Education

• Medical doctor: Faculty of Medicine, Udayana University, 2001

• Spesialist: Department of Child Health, Airlangga University, 2009

• Fellowship Allergy-Immunology: Department of Child Health, VuMC-AMC, Netherland, 2013

• Consultant: Department of Child Health, Indonesia University, 2017

Position

Staff of Allergy-Immunology Division, Department of Child Health Faculty of Medicine Udayana University/Udayana University Hospital

Organization

• Member, Indonesian Medical Association

• Member, Indonesian Pediatric Society

• Member, Allergy-Immunology Working Group Indonesian Pediatric Society

• Member, Indonesian Society of Allergy and Immunology

B-Cell Symposium, August 10, 2019

Komang Ayu Witarini

Division of Alergy-Immunology, Child Health Department, Faculty of medicine Udayana University/Udayana University Hospital

THE NEW INSIGHT IN

MANAGEMENT OF COW ’ S MILK PROTEIN ALLERGY

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OUTLINE

B-Cell Symposium, August 10, 2019

• Introduction

• Approach to cow’s milk protein allergy

• Cow’s milk protein allergy Guideline

• Feeding option in cow’s milk protein allergy

• Cow ’ s milk products

• Evaluation

• Prevention

• Conclusions

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• Cow’s milk and egg are the most common food allergen in infant and young Asia children¹

• Sensitization on atopic dermatitis patients in Pediatric Allergy Clinic RSCM Hospital² and Sanglah Hospital³

1. Lee AJ, Thalayasingam M, Lee BW, Asia Pac Allergy 2013;3(1):3-14 2. Munasir ZM, Muktiarti D. Asia Pac Allergy. 2013; 3(1): 23–8

3. Witarini KA [Tesis]. Jakarta:FKUI, 2017

White egg (31%) Cow’s milk (23,8%) Chicken (23,8%) Yolk egg (21%) Nuts (21%)

RSCM Pediatric Allergy Clinic (2013)

Egg (36,4%)

Cow’s milk (36,4%) Soy (36,4%)

Shrimp (27,3%) Oyster (27,3%)

Sanglah Pediatric Allergy Clinic (2017)

B-Cell Symposium, August 10, 2019

INTRODUCTION

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• Cow’s milk protein allergy (CMPA) is defined as an immune-mediated adverse reaction to cow’s milk protein

- Must be distinguished from a variety of adverse reactions to CMP that do not have an immune basis but may resemble it in clinical

manifestations

• Most of them diagnosed before 1 year of age

• CMPA had great impact on the patient if mistreated

Introduction…

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History Clinical

manifestations

Allergy test

- Confirmed allergy with an allergen(s) 

specific avoidance/

immunotherapy - Prevent unnecessary

avoidance

Elimination Provocation and

Test

APPROACH TO CMPA

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Skin

Atopic dermatitis, urticaria, angioedema

Respiratory tract Rhinitis, asthma

Gastrointestinal

Nausea, vomit, diarrhea, Rectal bleeding

Systemic Anaphylactic Sign and

symptoms…

Host A,.Ann Allergy Asthma Immunol .2002;89:33–7 DRACMA, WAO, 2010

Clinical Manifestation

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Prevalece of allergic symptoms

Atopic dermatitis

Asthma

0 1 3 7 15 year

Adapted from holgate S,Church MK. eds. Allergy, London: Gower Medical Publishing, 1993

Allergic rhinitis

Food allergy

• Typical sequence of allergic symptoms

• Appearing during early childhood, persist over years or decades

• Often remit

spontaneously with age

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Atopic March

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COW’S MILK PROTEIN ALLERGY GUIDELINE

B-Cell Symposium, August 10, 2019

Algorithm for the diagnosis CMPA

in exclusively breast-fed infants Suspicion of CMPA

History, clinical examination, risk factors

Mild/moderate CMPA

Continue breastfeeding, avoid cow’s milk and its products in mother’s diet (2-4 weeks)

Improvement (+)

Reintroduce cow’s milk in mother’s diet Symptoms (+)

CMPA

Symptoms (-)

Consider other etiology

Improvement (-)

Severe CMPA

Refer IgE Specific/SPT of CMP

Allergy Immunology Working Group, Indonesian Pediatric Society, 2010 ¹⁰

Algorithm for the diagnosis CMPA in formula fed infants

Suspicion of CMPA

History, clinical examination, risk factors

Mild/moderate CMPA

Extensively hydrolyzed formula (2-4 weeks)*

Improvement (+) Open challenge Symptoms (+)

CMPA

Symptoms (-) Consider other

etiology

Improvement (-) Amino acid formula

Or consider other etiology

Severe CMPA Refer Amino acid

formula IgE Specific/SPT of CMP

* Soy based formula can be used in infants 0-12 months of age if there is tolerability/cost/

availability issue

Allergy Immunology Working Group, Indonesian Pediatric Society, 2010 11

MILD/MODERATE CMPA

One/more following symptoms:

- GI tract: frequent

regurgitation, vomiting, diarrhoea, constipation

(with/without perianal rash), blood in stool

- Iron deficiency anemia - Skin: dermatitis atopic,

urtikaria, angioedema - Rhinitis, asthma

- Persistent colic (> 3 hours daily, at least 3 days/week, over a period of 3 weeks)

SEVERE CMPA

One/more following symptoms:

- Failure to thrive because of diarrhoea/regurgitation/vomit ing/refusal to feed

- Moderate/large amount of blood in the stool with

decreased haemoglobin

- Protein-lossing enteropathy - Severe DA with

anemia/hypoalbuminemia/fail ure to thrive

- Laringoedema or bronchus obstruction

- Anaphylactic shock

Allergy Immunology Working Group, Indonesian Pediatric Society, 2010 12

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FEEDING OPTION IN COW’S MILK PROTEIN ALLERGY

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Protein In Cow’s Milk

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Fraction/protein Allergen

[1] g/l ~30 % Total

protein 80 MW

(kDa) AA PI

Caseins

Alpha_s1-casein 12-15 29 23.6 199 4.9-5.0

Alpha_s2-casein 3-4 8 25.2 207 5.2-5.4

Beta-casein 9-11 27 24.0 209 5.1-5.4

Gamma₁-casein Bos d 8 20.6 180 5.5

Gamma₂-casein 1-2 6 11.8 104 6.4

Gamma₃-casein 11.6 102 5.8

Kappa-casein 3-4 10 19.0 169 5.4-5.6

~5.0 20 Whey proteins

Alpha-lactalbumin Bos d 4 1-1.5 5 14.2 123 4.8

Beta-lactoglobulin Bos d 5 3-4 10 18.3 162 5.3

Immunoglobulin Bos d 7 0.6-1.0 3 160.0 - -

BSA Bos d 6 0.1-0.4 1 67.0 583 4.9-5.1

Lactoferrin - 0.09 traces 800.0 703 8.7

AA = Amino acids; BSA = bovine serum albumin.

Protein Hydrolysates: Different Types

Allergenicity

intact protein pHF eHF Amino acids

Prevention

Treatment

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Extensively Hydrolyzed Formula

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• Contains only peptides that have a MW <3,000 d

• >90% tolerance in IgE-CMPA

• First choice for cows milk substitution, especially in infants under 6 months old

• Bitter, expensive

Greer FR, et al. Pediatrics 2008;121:183-91

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Growth in children with eHF

No long-term consequences of different formulas on BMI

were observed

Note:

• Solid blue line, pHF-W (partially hydrolyzed whey

• Solid green line: eHF-W (extensively hydrolyzed whey

• Solid red line: eHF-C (extensively hydrolyzed casein

• Solid yellow line: CMF (cow-milk formula)

• Gray line:BF (exclusively breastfed for 16 wk

• Dashed red line: 95% prediction band around the trajectory of the eHF-C study group

Am J Clin Nutr. 2009;89:1846–56.

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Amino Acid Formula

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Greer FR, et al. Pediatrics 2008;121:183-91

• Peptide-free formulas that contain mixtures of essential and nonessential amino acids

• Lack allergenicity

• First choice for CMPA patients with severe allergic reaction

• Expensive

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Soy Formula

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• <10% soy allergy among IgE-CMPA

• Soy formula can be use as cow’s milk substitution in patients with IgE-mediated CMPA, age 0-12 months (Indonesian guideline)

• In Australian guidelines:

• Soy formula is recommended as first choice for infants with immediate food reactions, and for those with

gastrointestinal symptoms or atopic dermatitis in the absence of failure to thrive

DRACMA, WAO, 2010 MJA 2008; 188: 109–112

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Growth in Children with Soy Formula

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J Nutr 2004;134:1220S-24S

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Commercial Foods that Frequently Contain Unexpected Allergens

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Foods Containing Milk Protein Breads and bread crumbs

English muffin Flavored crackers Nondairy creamer Instant noodle cups Sorbets

Soy cheese Waffles

Canned fish

Baby foods with mixed ingredients

Most mammalian milks cross-react with cow's milk (e.g. sheep, goat)

Pediatric allergy: principles and practice. 2^ndedition

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Label Reading

B-Cell Symposium, August 10, 2019

Pediatric allergy: principles and practice. 2^ndedition

Milk Milk

Artificial butter flavor, butter, buttermilk

Casein (rennet), caseinates (calcium, magnesium, potassium, and sodium) Ghee

Hydrolysates (casein, milk, protein, and whey)

Lactalbumin, lactoglobulin, lactose (maycontain), lactulose Milk solids, milk powder, nonfat dry milk powder

Whey

Label ingredients that may indicate the presence of milk protein Chocolate

Flavorings (artificial, caramel, and natural) High-protein flour

Luncheon meats Margarine

Takaran Saji : 1 Bungkus (30g) Jumlah Sajian peKemasan : 0,5 JUMLAH PERSAJIAN

Energi Total 160 kkal Energi dari Lemak 50 Kkal

%AKG

Lemak Total 5 g 8 %

Lemak jenuh 2 g 10 %

Kolesterol 0 mg 0 %

Protein 3 g 6 %

karbohidrtat Total 20 g 7 % Serat Pangan

Gula Natrium

2 g 1 g 216 mg

8 % 13

%

Kalium 51 mg 1 %

Vitamin A 0 %

Vitamin C 0 %

Kalsium 0 %

Zat Besi 0 %

Informasi Nilai Gizi

KOMPOSISI: Tepung Terigu, Lemak Nabati, Gula, Garam, Perisa Daging Asap, Keju Bubuk, Whey Bubuk, Ragi,

Penguat Rasa Monosodium Glutamat, Daun Bawang Kering, Penguat Rasa Hidrolisat Protein Sayuran, Pewarna

Makanan, Tartrazin Cl 19140.

ContohProduk

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ContohProduk

KOMPOSISI: Beras, Jagung, Dektrosa, Minyak Nabati, Gula, Bubuk Kedelai, Bubuk Whey, Telur Bubuk, Penguat Rasa (MSG), Garam.

Takaran Saji :

Jumlah Sajian per Kemasan :

25 g 2

JUMLAH PERSAJIAN Energi Total

Energi dari Lemak

160kkal 50Kkal

Lemak Total Protein Karbohidrtat Total Natrium

3g 2g 20g 70mg

%AKG 5%

4%

6%

3%

Informasi NilaiGizi

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ContohProduk

KOMPOSISI: Beras, Protein Soya, Susu Full Cream, Susu Skim, Minyak Soya, Minyak Bawang, Lesitin Soya, Daging Ayam, Jagung Manis, Bumbu, Premix

Vitamin dan Premix Mineral.

Takaran Saji

Jumlah Sajian per Kemasan

1 sachet (25g)

4 JUMLAHPERSAJIAN

Energi total 100 kkal Lemak Total Omega 3 Omega 6 Lestin Karbohidrat total Serat Makanan PrebiotikFOS Gula Protein

1.5 g 0.07 5 g

0.25 g A0.1

0 g 19 g 1 g 0.5 g 1 g 3g

Informasi Nilai Gizi

10% Asam folat 4 % 25% Asam Pantotenat 40 %

%AKG Protein Vitamin A Vitamin D Vitamin E Vitamin K Vitamin C Vitamin B1 Vitamin B2 Vitamin B6

50% Biotin 15% Kolin 40% Inositol 30% Natrium 15% Kalsium 20% Zat Besi 15% Kalium Vitamin B12 60% Yodium

3.75 Mcg 12.5 mg 5 mg 20 % 15 % 30 % 8 % 15 %

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ContohProduk

KOMPOSISI: Beras Merah, Kedelai, Gula, Minya Kelapa Sawit, Mineral, Premiks Vitamin, Pengemulsi Lesitin

Kedelai, dan Vanila. Dapat

Mengandung sekelumit protein susu dan/atau gluten.

Takaran saji 3 sendokmakan(30 g) Jumlah Sajianperkemasan:sekitar2 JUMLAHPERSAJIAN

Energi Total 230kkal

4.5g 1.5g 8g 14 g Lemak

Asam Linoleut Protein Karbohidrat 34 g Serat Pangan 2 g Gula Natrium 6.5 mg Protein Vitamin A Vitamin D Vitamin E Vitamin B1 (Tomin) Vitamin B2 Vitamin B3 Vitamin B5 Vitamin B6 Vitamin B9 Vitamin B12 Vitamin C Kalsium Fosfor Zat Besi Yodium Zink

%AKG 34%

40%

50%

30%

40%

40%

40%

40%

100%

15%

50%

65%

45%

55%

50%

25%

25%

Persajianmengandung:

Kalsium/Fosfor 1.2

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EVALUATION

B-Cell Symposium, August 10, 2019

Natural course of CMPA

First Year Second Year Third Year

45-55% 60-75%

90%

90%

Outgrown

Arch Dis Child. 2007;92;902-8 Med Clin N Am 2006;90:97-127

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Evaluation…

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Periodic Review

• Periodic review every 6 months

• Open challenge – Symptoms (+):

• Still allergy  avoidance

• Review another 6 months – Symptoms (-)

• Tolerance  reintroduce cow’s milk

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PREVENTION

B-Cell Symposium, August 10, 2019

As management should involve prevention:

Identification those with allergic risk

EXCLUSIVE BREAST FEEDING Partial Hidrolisat Formula

5-15%

jika orangtua tidak memiliki

riwayat alergi

25%-30%

jika saudara memiliki riwayat alergi

20%-30%

jika salah satu orangtua memiliki

riwayat alergi

40%-60%

jika kedua orangtua memiliki

riwayat alergi

60%-80%

Jika kedua orang tua memiliki manifestasi

sama

Risiko Alergi

Riwayat Keluarga AlergiPositif

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Efficacy of Prevention

B-Cell Symposium, August 10, 2019

10pHF versus cow's milk formula in high risk infants.

significant reduction in infant allergy (7 studies, 2514 infants; typical RR 0.79, 95% CI 0.66, 0.94), but not in the incidence of childhood allergy (2 studies, 950 infants; typical RR 0.85, 95% CI 0.69, 1.05).

Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003664

Meta-analysis: on partially hydrolyzed formula

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Efficacy of Prevention

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Efficacy of Breast Feeding

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CONCLUSIONS

B-Cell Symposium, August 10, 2019

• Management of CMPA is strict avoidance of cow’s milk protein and its products.

• Feeding options:

– Extensive hydrolyzed formula – Amino acid formula

– Soy formula

• Periodic review is needed to prevent unnecessarily prolonged elimination diets

• Prevention on infant with allergic risk reduced prevalence of CMPA

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THANK YOU

B-Cell Symposium, August 10, 2019