FOOD ALLERGY AND IMMUNITY

ZAKIUDIN MUNASIR D I V I S I O N O F A L L E R G Y - I M M U N O L O G Y - D E P A R T M E N T O F C H I L D H E A L T H

U N I V E R S I T Y O F I N D O N E S I A / C I P T O M A N G U N K U S U M O H O S P I T A L

DR. Dr. Zakiudin Munasir, SpA(K) Division of Allergy and Clinical Immunology, University of Indonesia, Jakarta, Indonesia

Doctor Zakiudin Munasir is Head of the Division of Allergy and Immunology, Department of Child Health in the Faculty of Medicine, University of Indonesia-Cipto Mangunkusumo Hospital. He completed his medical degree at the University of Indonesia, Jakarta, Indonesia and residency in paediatrics. Dr. Munasir subsequently became a pediatric consultant in allergy and immunology for the Indonesian Pediatric Society.

Dr Munasir is a member of the working group on allergy and immunology for the Indonesian Pediatric Society and also a member of the Indonesian Allergy and Immunology Association. He is a member of the European Pediatric Allergy Rheumatology, the World Allergy Organization, the European Academy of Allergy and. Clinical Immunology and board member of Asia Pacific Association of Pediatric Allergy, Respirology & Immunology (APAPARI) He is also an editor for the Asia Pacific Allergy Journal.

Background Increasing prevalence of allergic diseases.

Allergic diseases are most common chronic diseases in children and adults.

A European Declaration on Immunotherapy

The Rising Incidence of Atopic Dermatitis

Atopic dermatitis is now one of the most common childhood disorders in the Asia Pacific region.

Its prevalence has increased markedly in the past decade.

Adapted from Asher et al, 2006

Change in incidence of atopic dermatitis

Incidence of allergic diseases in Jakarta

0%

5%

10%

15%

20%

25%

Central Jakarta (1990) ISAAC East Jakarta (2001) EAAEL Jakarta (2006)

6.9%

8.9%

13.9%

9.0%

14.2%

12.3%

4.9% 3.9%

24.6%

Asthma Allergic rhinitis Atopic dermatitis

Courtesy of Dr. dr. Zakiudin Munasir, SpA(K) et al

Food Allergy Food allergy is one of most important allergic disease in children.

In fact, every food could induce allergy. However, there is different degree of allergenicity between each food.

Natural Imbalance Pregnancy and neonates

Th2 directed immune system: cytokines down regulate

◦ cellular-immunity (Th1) > no rejection of the fetus and or mother tissues

After birth

Development of their own “healthy” Th1/ Th2 balanced immune system

Th 1 Th 2

Normal

Pregnancies

Recurrent

Miscarriages

Failure

CD 69+

IL 2

TNF α

TNF δ

CD 94+

IL 4

IL 5

IL 10

Utrecht University

Th0 Th1/Th17 Th2

APC

Immune regulation Th1/Th2 paradigm

Allergy

Antibody-mediated autoimmunity

Resistance to intracellular

infections

Anti-cancer

Delayed type

hypersensitivity reactions

Resistance to

extracellular infections

Tolerance

T-cell mediated autoimmunity

Graft rejection

Utrecht University

Immune regulation The extended Th1/Th2 paradigm

IFN-

IL-12

IL-17

IL-22

IL-4

IL-5

IL-13

IL-10

TGF-

Th1 Th2 Th17 Treg

Utrecht University

Nutrition factors

1. Protein

• Immunoglobulin, complement, and immune cells synthesis.

2. Vitamin A

• Weak antioxidant, affects cytokine production, expression of retinoic acid receptors linked to T-cell antigen expression.

3. Beta-carotene, carotenoids

• Antioxidant, increases NK, T cells.

Nutrition factors

4. B vitamins

• Needed for DNA synthesis.

5. Vitamin C

• Antioxidant, electron transfer reactions,hydroxylation, facilitates iron absorption.

6. Vitamin E

• acts as a mitogen, antioxidant, interacts with selenium, affect fatty acid metabolism.

Nutrition factors

7. Cuprum

• Phagocyte and T cell function.

8. Iron

• Transferrin-bound iron essential for lymphocyte proliferation, can be deleterious because it used by bacteria.

9. Magnesium

• Granulocyte production and adhesion.

Inappropriate diet may cause malnutrition and immunocompromise

J Clin Allerg Immunol 2003; 112:S118-27

Allergic March

Barnetson RS, Rogers M. BMJ 2002;324:1376-9.; Tao Zheng, Allergy Asthma Immunol Res. 2011 April;3(2):67-73.

4 of 10 infants with atopic dermatitis develop

into asthma and allergic rhinitis in later time.

30–45% atopic dermatitis in infants are caused

by cow’s milk allergy.

Allergic Diseases Impacts Individual

Poor quality of life, sleep and emotion disruption,

low performance in work and school, and lack of

overall development.

High cost.

Society as a whole

High cost.

A European Declaration on Immunotherapy

Economic Impact of Allergic Diseases

• Inpatient and outpatient in hospital

• Physician service

• Drugs

• Diagnostic assessment

Direct Medical Cost

• Transportation

• Nursing tools at home

• Special diet

Direct Nonmedical Cost

• Absence in work and school

• Job loss

• Home modification

• Death

Indirect Cost

Direct Cost of Allergic Population in Europe (1998, euro)

Asthma 6.4 billion

Contact dermatitis 2.3 billion

Allergic rhinitis 1.3 billion

Food allergy [???]

Source: European allergy white paper (1997)

Cost Estimation of Allergic Diseases in Europe

A European Declaration on Immunotherapy

Cost of allergic diseases in Thailand

treatments typically involve substitution of the current

milk diet with different nutrition in addition to symptom-

atic treatments.

Monitoring and lab tests

Prick skin test and immunoglobulin E(IgE) blood test were

common tests included across all atopic conditions.

Additional tests included gastroscopy, colonoscopy,

intestinal biopsy, pH monitoring, complete blood count,

and stool culture, which were relevant specifically to the

gastrointestinal symptomsof the CMA.

Outpatient care

Outpatient careconsidered included routinevisitsto pedi-

atricians, specialists(i.e., allergist), and occasionally to the

emergency department.

Inpatient care

Inpatient care included hospitalization and visits to the

emergency department that led to inpatient admission.

Unit costs

Costspresented are in 2010 Thai baht (THB). Treatment

unit costs were obtained from the Pharmacy Department

at King Chulalongkorn Memorial Hospital. Costs of the

nutrition to treat CMA included in the model were only

the marginal costs to those of the current milk diet if the

children did not have CMA. Unit costs of each resource

use (i.e., physician visits, lab tests, hospitalization) were

obtained from a Thai standard cost list developed specifi-

cally for health technology assessment20.

Model inputs (unit costsand medical resource use) for

each atopic condition are shown in the Appendix.

Sensitivity analysis

In order to account for uncertainty in the model, a prob-

abilistic sensitivity analysis where key inputs including

prevalence rates, costs, severity distribution, and quantity

of resourceusewerevaried simultaneously from replication

to replication (i.e., 10,000 replications were run) by sam-

pling from probability distributions was performed.

Proportionsof patientsutilizing each resource and propor-

tions of severe cases among each atopic condition were

varied randomly according to a beta distribution, while

quantity of resource use, unit costs, and prevalence rates

were varied according to a gamma distribution, assuming

20% standard deviations around the mean. Univariate

deterministic sensitivity analysis was also performed in

four key parameters: prevalence, quantity of resource use,

unit costs, and, since severe cases are usually associated

with highest costscompared to mild and moderate condi-

tion, proportion of severecases. Each parameter wasvaried

according to the95% confidence intervals, assuming stan-

dard deviationswere 20% of the mean, while other var-

iableswere holding constant.

Results

By applying the prevalence ratesof 10.1%, 10.3%, 11.1%,

and 3.6% for atopic dermatitis, chronic rhinitis, asthma

(i.e., recurrent wheeze), and CMA, respectively, to the

number of Thai children aged 0–5 years in 2010 (i.e.,

5,315,800), 536,896 cases of atopic dermatitis; 547,527

cases of chronic rhinitis; 590,054 cases of asthma; and

191,369 casesof CMA were identified.

Table 1 presents the total annual medical direct costs

of atopic diseases for all four conditions, which were

estimated to be THB 27.8 billion (US$899 million).

Treatments contributed largest to the total costs (46%),

followed by inpatient care (37%), outpatient care (12%),

and monitoring and lab tests (5%). Comparing the costs

among the atopic conditions, CMA was associated with

the highest costs (44% of the total burden), followed by

chronic rhinitis (25%), asthma (20%), and atopic derma-

titis (11%).

The average yearly medical cost of atopic diseases per

patient isdisplayed in Table 2. CMA wasassociated with

the highest per-patient annual cost (THB 64,383;

US$2077), with treatments accounting for the largest

cost component (68%). Inpatient care accounted for

20% of the total direct costs, while outpatient care

accounted for 8%. Monitoring and lab tests contributed

only 4% of the total costs, but still represent total annual

expenditures of close to THB 500 million (US$16 mil-

lion). The second most costly condition was chronic

Table 1. Total costs reported by each atopic condition and resource use type (Thai baht).

Cow’s milk allergy Atopic dermatitis Chronic rhinitis Asthma Total

Treatment 8,341,687,056 1,196,131,898 2,817,077,750 332,018,553 12,686,915,258Inpatient care 2,536,430,074 302,636,404 3,192,266,056 4,249,845,324 10,281,177,858Outpatient care 950,664,178 901,069,644 610,167,031 932,432,025 3,394,332,879Monitoring and lab tests 492,205,418 516,524,685 317,065,112 169,704,205 1,495,499,421Total direct medical costs 12,320,986,726 2,916,362,632 6,936,575,950 5,684,000,107 27,857,925,415

Journal of Medical Economics 2012

4 Direct medical cost of atopic disease in Thailand Ngamphaiboon et al. www.informahealthcare.com/jme ! 2012 Informa UKLtd

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Total costs reported by each atopic condition and resource use type (Thai baht).

rhinitis, with an estimated per-patient annual cost of

THB 12,669 (US$409). The majority of the costs were

associated with inpatient care (46%) and treatments

(41%). Costsof outpatient care and monitoring and diag-

nostic tests accounted for only 9% and 4%, respectively.

Annual cost per child with asthma wasestimated at THB

9633 (US$312), slightly lower than the cost of chronic

rhinitis. The main cost driver for asthma was related to

inpatient care (75%), followed by outpatient care (16%),

treatments(6%), and then monitoringand laboratory tests

(3%). Atopic dermatitis was estimated with the lowest

annual per-patient cost (THB 5432; US$175). The aver-

age treatment cost that was the largest cost component,

representing 41% of the total costs, wasestimated at THB

2228 (US$72). Outpatient care accounted for 31% and

monitoring and diagnostic testsfor 18%. Sinceatopic der-

matitis isgenerally managed on an outpatient basis, inpa-

tient care costsaccounted for only 10% of the total costs.

Probabilistic sensitivity analysis revealed a 95% confi-

denceinterval of thetotal direct medical costsranged from

THB 22.1 billion (US$712 million) to THB 29.7 billion

(US$957 million). In addition, the results from the

univariate sensitivity analysis are graphically shown as a

tornado diagram in Figure 2. In all scenarios, varying

parameters to the lower bound of the 95% confidence

interval resulted in a decrease in the total annual direct

medical costs. Reciprocally, increasing the parameters to

theupper boundsconsistently increased theresulting total

costs. The top three parameters that had the most influ-

ence on the total medical direct costswere thequantity of

treatmentsused, treatment costs, and prevalenceof CMA.

Varying the amount of treatments consumed from the

lower bound to the upper bound of its 95% confidence

interval fluctuated the total direct costs from THB 23.4

billion (US$754 million; decreased by 16%) to THB 33.3

billion (US$1074 million; increased by 20%), respec-

tively. Similarly, the total medical direct costs decreased

to THB 23.4 billion (US$756 million) and increased to

THB 33.2 billion (US$1072 million) when treatment

costs were varied from the lower to the upper bounds of

its 95% confidence interval. Lowering the prevalence of

CMA to thelower bound (i.e., 2.3%) wasassociated with a

decrease in the total direct costs to THB 23.4 billion

(US$755 million), whereasthe total direct costsincreased

to THB 33.0 billion (US$1064 million) when the preva-

lence increased to 5.1%.

Lowering theaveragequantity useof inpatient and out-

patient care to the lower bound decreased the total direct

costs by 13% and 4%, respectively, while increasing the

average quantity to the upper bound increased the total

direct costsby 16% and 5%. Varying the average quantity

use in monitoring and lab tests had the smallest impact

compared to variations in the inpatient care, outpatient

care, and treatments utilization. This resulted in the

change from 2% (negative sign indicates a decrease in

the total costs from base case) to 2%.

Variation in inpatient and outpatient care costs is

shown to have a relatively moderate effect on the total

direct costs. Decreasing unit costs of inpatient care (i.e.,

hospital per diem cost) and outpatient care (i.e., cost per

visit) resulted in reduction in the total costs by 13% and

4%, respectively. An increase in inpatient or outpatient

care unit costsresulted in an increase in the total costsby

14% and 5%, respectively.

Regardingtheprevalence, whereasvaryingtheinput on

prevalence of CMA had substantial impact on the results,

smaller impacts are observed when varying prevalence of

chronic rhinitis (i.e., total costs were varied by 9% to

11% for lower and higher prevalence, respectively),

followed by that of asthma (by 7% to 9%) and atopic

dermatitis ( 4% to 4%), respectively.

Theresultsfrom thebasecasehaveshown that thecost

of monitoring and lab testscontributed to only 5% of the

total direct cost. Variation in the unit cost of monitoring

and lab tests over the 95% confidence interval slightly

affected the total direct cost, resulting in the changes of

up to 2% compared to base case results.

Although severe cases are associated with highest cost

compared to illness with milder severity, varying the pro-

portion of severecasesin each atopic condition had shown

only a limited impact to the total costs. Varying this

parameter for each atopic condition resulted in a decrease

or an increasein thetotal costsby only up to 3% compared

to the base case.

Discussion

Atopic diseasesimpose asubstantial burden on healthcare

resources in Thailand as shown by the results from

Table 2. Average direct medical costs per treated patient (Thai baht).

Cow’s milk allergy Atopic dermatitis Chronic rhinitis Asthma

Treatment 43,590 2228 5145 563Inpatient care 13,254 564 5830 7202Outpatient care 4968 1678 1114 1580Monitoring and lab tests 2572 962 579 288Direct medical costs (per treated patient) 64,383 5432 12,669 9633

Journal of Medical Economics 2012

! 2012 Informa UKLtd www.informahealthcare.com/jme Direct medical cost of atopic disease in Thailand Ngamphaiboon et al. 5

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Average direct medical costs per treated patient (Thai baht).

Ngamphaiboon J, et al. J Med Econ. 2012;15:1025-35.

Food Allergy Food allergy is one of most important allergic disease in children.

In fact, every food could induce allergy. However, there is different degree of allergenicity between each food.

Cow’s milk protein is the second most common food allergen in young Asian children, after egg.

Indonesia national data is lacking.

Sensitization on atopic dermatitis patients in Pediatric Allergy Clinic (2011, 2013)

Food Allergy - Prevalence

Pediatric Allergy Clinic, RSCM, 2013

White egg (31%)

Cow’s milk (23.8 %)

Chicken (23.8%)

Yolk egg (21.4%)

Nuts (21%)

Wheat (21.4%)

Pediatric Allergy Clinic, RSCM, 2011

Maize

White egg

Tuna

chicken

Cow’s milk

Nuts

1. Lee AJ, Thalayasingam M, Lee BW, Asia Pac Allergy 2013;3:3-14

2. Sidabutar S, et al. Sari Pediatri. 2011;13:147-51.

3. Munasir ZM, Muktiarti D. Asia Pac Allergy. 2013; 3: 23–8.

CMPA-suspected symptoms Common infant presentations in

cow’s milk allergy

Atopic dermatitis Infantile colic Gastro-

esophageal reflux Other GI

symptoms

Milk diarrhea and rectal bleeding

Vomiting, chronic diarrhea, failure to

thrive

Apps JR and Beattie RM, BMJ 2009:339:b2275

How to Prevent Allergic Diseases?

Allergic Diseases Prevention

Allergy Primary Prevention

Identify High Risk

Evidence-based on Allergy Prevention (Guideline for allergy prevention in Germany by the Task Force on Allergy Prevention - German Federal Ministry of Health and Social Security)

CR, Cochrane review; MA, meta-analysis; RCT, randomized controlled trial; CS, cohort study; CC, case-control study

Muche-Borowski C. Allergy prevention. Dtsch Arztebl Int. 2009; 106: 625–31.

Environmental Modifiers in Allergic Disease

Prescott S, Nowak-Wegrzyn A. Ann Nutr Metab 2011;59:28–42.

Nutrition Factor in Allergy Prevention Nutrition Recommendation

Breastfeeding Infants should be exclusively breast-fed in the first four months to

prevent atopic diseases

Maternal nutrition during

pregnancy and/or

breastfeeding

Balanced and fully nutritious diet is recommended during pregnancy

and breastfeeding.

There is no well-documented evidence favoring a recommendation for

any type of dietary restriction during pregnancy or breastfeeding

(avoidance of potent dietary allergens)

Feeding of children at

risk with mother’s milk

substitutes

Infants at high risk of allergic disease should be given hydrolyzed

formula (partially or extensively hydrolyzed formula).

Soy-based infant formula is not recommended for the purpose of

allergy prevention.

Introduction of solid

food in the first year

Introducing complementary solid foods from around 4–6 months, with

no specific avoidance of allergenic foods.

Muche-Borowski C. Allergy prevention. Dtsch Arztebl Int. 2009; 106: 625–31. ; Prescott S, Nowak-Wegrzyn A. Ann Nutr Metab 2011;59:28–42.

Decision making: 1. “ benefit > risk” 2. low “cost” 3. “applicable”

Choices of Nutrition for Allergy Prevention

1. Breastfed

2. Soy Protein Formula

3. p-Hydrolyzed Whey

4. p-Hydrolyzed Casein

5. e-Hydrolyzed Whey

6. e-Hydrolyzed Casein

APPLICABILITY

+

+

+

+

+

+

LOW COST

+

+

+

+

-

-

LOW RISK

+

-

+

+

+

+

BENEFIT

+

-

+

-

-

+

Hydrolyzed Formula

Arch Pediatr Adolesc Med. 2005;159:810-6

Hydrolyzed Formula Systematic review (2005):

◦ Extensively hydrolyzed casein formulas (eHF-C) and partially hydrolyzed whey formulas (pHF-W) are appropriate alternatives to breast milk for allergy prevention in infants at risk.

◦ The use of these formulas in the general population should be considered, and one must weigh cost, compliance, and long-term benefits.

Arch Pediatr Adolesc Med. 2005;159:810-6

Hydrolyzed formula (German Infant Nutrition Study)

Adjusted cumulative incidence of parent-reported physician-

diagnosed eczema

Von Berg A, et al. J Allergy Clin Immunol. 2013 Jun;131(6):1565-73

ECONOMIC IMPACT OF NUTRITION INTERVENTION AS ALLERGIC PREVENTION

Conclusions Primary prevention of allergic diseases should be started in early life.

If breastfeeding is not possible, a partially hydrolyzed formula (pHF-W) is cost-effective for infants at high risk of allergic disease.

Primary

Allergy

Prevention

for Better

Indonesia

Generation

Thank You..