Koletzko Allergy Prevention Singapore 2011

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Preventing allergy by nutritional intervention

Sibylle Koletzko

Dr. von HaunerschesKinderspital,

Ludwig-Maximilians-

University Munich

Objectives

● Epidemiology of allergy and the hygiene hypothesis

● Possible allergy prevention by nutritional intervention

● Maternal diet during pregnancy and breast-feeding

● Breast-feeding

● Soy formula

● Hydrolysed formula (the GINI-study)

● Supplementary feeding

The prevalence of the differentallergic diseases in relation to age

0 ½ 1 3 7 15

Age (years)

P r e v a l e n c e

foodallergy

atopicdermatitis

asthma

allergic rhinitis

Rising prevalence in the 70ies-90ies of allergicdiseases in children living in middle Europe

von Mutius

Atopy and exercise-induced bronchospasmin Ghana: 1993-2003

0

2

4

6

8

10

12

14

16

Atopy EIB

%1993

2003

P<0.001

P=0.004

EOD Addo Yobo & A Custovic, 2006



2

Atopy and exercise-induced bronchospasmamongst urban rich, urban poor and rural

children in Ghana in 1993

0

2

4

6

8

10

12

Urban Rich Urban poor Rural

Atopy

EIB

EOD Addo Yobo & A Custovic, Thorax 1997

Infections and chronic inflammatory disease

Hepatitis A

Measles

Rheumatic fever

Tuberculosis

Mumps

Crohn´sdisease

Multiplesclerosis

Type 1diabetes

Asthma

J. F. Bach, NEJM 2002

Hygiene Hypothesis

Improved hygienic conditions

Less microbial exposure during earlychildhood

Slower post-natal maturation of the immune

system

Delayed development of the optimal balancebetween TH-1 and TH-2-like immuneresponse

Stachan, BMJ 1989

Type of food,

breast feeding

Age

Bacteria,

probiotics

Antibiotics,drugs

Gut flora

Fibres, prebiotics

Maternal gut flora

Mode of delivery

Genes, receptors

Factors influencing the gut flora

Developmental deviations of Th-cell cytokine profiles in

infants indicating future atopic sensitization and allergy

Based on data from Patrick G. Holt and coworkers, Perth, Western Australia (Clin. Exp. Allergy. 1998; 28 Suppl. 5: 39-44, Lancet1999; 353: 196-200)

Sensitization(IgE antibodies)

Tolerance

Atopic

disease

Atopicchild

Healthychild

Age monthsBirth 3 6 12 18 24

Th2:Th1ratio

R e l a t i v e T - c e l l m e m o r y

r e s p o n s e p a t t e r n s

Window forfine-tuning

Possible nutritional approaches forprimary prevention

WHEN: Prenatal – postnatal?

To WHOM: Maternal diet during pregnancy and lactation?

Nutritional intervention in infant?

All infants? High risk infants?

HOW: Elimination or supplementation?



3

Who is at high risk for allergy?

Risk depends on family history

85 %2 parents + 1 sibling

75 %2, same manifestation

40 %2 with allergic disease

20 %1 with allergic disease

5 %None

Risk for offspringParental allergy

Kiellman, JACI 1999

Critical review on nutritional measure forprevention of allergy

• Epidemiological data

• Observational studies

• Interventional studies

• To assess a cause-effect-relationship, only prospectiveinterventional studies are appropriate (no retrospective,no cross-sectional, no prospective non-interventional)

• Maternal exclusion diet during pregnancy and lactation

• Breastfeeding

• Delayed introduction of solid foods to infant

• Soy or hypoallergenic infant formula

• Supplementary feeding

Possible nutritional approachesfor primary prevention

Maternal diet during pregnancy

0.71 (0.34-1.49)Any atopic condition in first 18 mon.(1 RCT, n=163)

1.01 (0.20-5.15)Allergic urticaria in first 18 months

(1 RCT, n=163)

2.2 (0.4-13)Asthma in first 18 months(2 RCTs, n=334)

1.01 (0.6-1.8)Atopic eczema in first 12-18 months(2 RCTs, n=334)

RR (95% CI)Outcome measure

Kramer, Kakuma. Cochrane Review 2006

Favours elimination diet 1 Favours regular diet

-1.4 (-7 to 4.4)Eczema activity score(1 RCT, n=34)

-0.8 (-4.4 to 2.8)Eczema area score

(1 RCT, n=34)

WMD (95% CI)Outcome measure

0.7 (0.3-1.7)Atopiceczema in first 18 mo

(1 RCT, n=26)

RR (95% CI)Outcome measure

Favours e l im inat ion d ie t 1 Favours regu lar d ie t

1

Maternal diet during breast-feeding Conclusions: Maternal diet

• Recommended: balanced and nutritional complete

diet during pregnancy and breast-feeding

• No evidence for dietary restrictions (avoidance of potential

food-allergens) during pregnancy and breast feeding (A)

• Some evidence for protective effect of fish

consumption during pregnancy and breast-feeding for

development of atopic diseases in offspring (B)

ESPGHAN1999, 2008 American Academy of Pediatrics (AAP) 2008

Deutsche Ges Kinder- und Jugendmedizin 2008 Leitlinien Allergieprävention 2009



4

Does breast-feeding reduces the risk for allergy?

• Very conflicting data whether any, prolonged or

exclusive breast-feeding reduces the risk for

allergic diseases.

• Evidence mostly from observational studies,

(reverse causality is likely)

Breast-feeding: no protection against asthmaUS Agency for Healthcare Research and Quality, 2007

??

Exclusive breast-feeding for at least 3 months doesNOT reduce the risk for later atopic dermatitis

Conclusion: Breastfeeding

• There are many good reasons to promote

breastfeeding during the first half year of life.

• The available knowledge does not support the

evidence that prolonged or exclusive

breastfeeding reduces the risk for atopic

dermatitis, asthma or allergic rhinitis.

Formulae for infants

Intact Protein Partial ly hydrolyzed Extensively hydrolyzed Amino acid formula

Allergenicity

WheyCasein

Cow’s milk formulaSoy formulaGoat’s milk formula

HA-formulaWheyCasein

For treatment of cow’s milk allergy

• „Feeding with a soy formula cannot be

recommended for prevention of allergy or

food intolerance …“

Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in

infants.Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003741

Soy formula:no benefit for allergy prevention



5

Depending on the degree of enzymatic hydrolysis,

ultraheating and ultrafiltration classified as

partially hydrolysed formula (pHF) (18% >6000 Dalton)

extensively hydrolysed formula (eHF) (0.5-2% >6000 Dalton)

and

depending on the protein source

whey or casein hydrolysate

Hypoallergenic protein hydrolysates Hydrolysed formulae: Major questions

• Are hydrolysed cow‘s milk based formulae able to reducethe incidence of allergic diseases?

• Short- or long-term effect?

• Is the starting protein (whey/casein) and/ or the degreeof hydrolysation important for the effect?

• Is the effect dependent on the family history for atopy?

• Does nutrition in early life have any influence on the

particular type of allergic manifestation?

German Infant Nutritional Intervention study

Objective of the studyTo investigate the allergy preventive effect of three different

hydrolysed formulas compared with a regular cow’s milk based

formula in the first three years of life in children at risk of allergic

diseases.

The study is supported by the German Federal Ministryfor Education, Science, Research and Technology, grant no 01EE 9401-4

Recruitment and study design

5991 healthyterm neonatesborn 1995-1998

Pos. familyhistoryof allergy Pos. family history, but refusal

Neg. family history of allergy

Intervention group: n=2252breastmilk +/- 4 study formulae

Non-Intervention group: n=3739breastmilk +/- free formula

•Formula used for intervention

Hydrolysates:

Partially hydrolysed whey formula pHF-W

NAN HA®Extensively hydrolysed whey formula eHF-W

Nutrilon pepti®Extensively hydrolysed casein formula eHF-C

Nutramigencompared with

Regular cow‘s milk based formula CMF

Blinded formulas of the GINI study,

4 letters for each kind of formula

Feeding recommendations in theintervention group

• Breastfeeding for at least 4, better 6 months.

• Feeding the randomised study formula as only supplement

for breastfeeding during intervention period of 4 months

• No solids within the first 4 months.

• Thereafter, only one new solid food per week.

• No potentially allergenic foods as whole cow‘s milk and

diary products, hens‘s egg, fish, nuts, and citrus during the

first year of life.



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Feeding characteristics in intervention group:Distribution of study formula and human milk

excl. study formula

study formula +human milk

excl. human milk

0

20

40

60

80

100

CMF

n=453

pHF-W

n=455

eHF-W

n=456

eHF-C

n=446

%

n= 1810

Non-intervention, pos. family historyNon-intervention, neg. family history

HR 1.9 (95% CI 1.5-2.4)

Intervention, pos. family history

Adjusted cumulative incidence of physician diagnosedatopic dermatitis in fully breast-fed infants with positiveand negative family history of atopy

v. Berg et al. Clin & Experimental Allergy 2009

Significant different characteristics between fullybreastfed & partly or non-breastfed children in theintervention & non-intervention group

0

10

20

30

40

50

60

70

80

U r b a

n a r

e a

S c h o

o l > 1 0

P e t k

e e p i

n g

M a t e

r n a l

s m o k

i n

S o l i d

s < 4 m

o

E g g , C P M

fully BF Int mixed/no BF Int fully BF Non-Int mixed/no BF Non-Int

J Pediatr 2004;104:602-7

*

*

*

*

* *

* *

*

*

* *

* p<0.05

%

*p < 0.05 forpHF-W and eHF-Cvs CMF

*

*

*

*

**

Cumulative incidence of atopic dermatitisin the 4 intervention groups (per protocol analysis)

v. Berg, Koletzkoet al. J ACI 2003;111:533-40

0

5

10

15

20

25

birth first second third year

CMF pHF-W

eHF-W eHF-C

Adjusted cum. Incidenz von Arztdiagnose

N=402

N=889 p h y s i c i a n d i a g n o s e d e c z e m a [ a d j . % ]

age [years]1 2 3 4 5 6

6

0

7

0

8

0

9

0

10

0

15

0

20

0

25

0

30

0

35

0

40

00

NI:

NI:NI pos. family history

NI neg. family history

NI pos. family history

NI neg. family history

HR 2.1 (95% CI 1.6-2.7)

Adj. cumulative incidence of physician diagnosed atopic dermatitis

in formula-fed infants with pos. and neg. family history for atopy

NI = non-intervention, formula freely chosen by mother



I non compliant, HR 2.7 (95% CI 1.9-3.9)

I CMF, HR 2.6 (95% CI 2.0-3.5)

NI FH+, HR 2.1 (95% CI 1.6-2.7)

NI FH-,

NI non-InterventionI =Intervention

N=402

N=889 p h y s i c i a n d i a g n o s e d e c z e m a [ a d j . % ]

age [years]1 2 3 4 5 6

6

0

7

0

8

0

9

0

10

0

15

0

20

0

25

0

30

0

35

0

40

00

NI:

NI:

N=224

N=118

I: CMF

I: non-compliant

Adj. cumulative incidence of physician diagnosed atopic dermatitis

in formula-fed infants with pos. and neg. family history for atopy

NI = non-intervention, formula freely chosen by mother

Pos. familiy history

Neg. family history




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I non compliant, HR 2.7 (95% CI 1.9-3.9)I CMF, HR 2.6 (95% CI 2.0-3.5)

I eHF-W, HR 1.9 (95% CI 1.4-2.6)

I pHF-W, HR 1.6 (95% CI 1.2-2.3)

I eHF-C, HR 1.3 (95% CI 0.9-1.9)

NI FH+ fb-, HR 2.1 (95% CI 1.6-2.7)

NI FH-fb-, 1.0

NI = non-Intervention

I =Intervention

N=224

N=180

N=211

N=118

N=204

N=402

N=889 p h y s i c i a n d i a g n o s e d e c z e m a [ a d j .

% ]

age [years]

6

0

7

0

8

0

9

0

10

0

15

0

20

0

25

0

30

0

35

0

40

00

NI:

I: CMF

I: eHF-C

I: eHF-W

I: non-compliant

I: pHF-W

NI:

1 2 3 4 5 6

Adj. cumulative incidence of physician diagnosed atopic dermatitisin formula-fed infants with pos. and neg. family history for atopy

Pos. familiy history

Neg. family history


Comparison vs CMF All allergies Atop. dermatitis Asthma &allergic rhinitis

Part. Hydrol. Whey ↓ 0.8(0.7–0.96)

↓ 0.8(0.7–0.97)

NS

Ext. Hydrol. Whey NS NS NS

Ext. Hydrol. Casein ↓ 0.8(0.7–0.9)

↓ 0.7(0.6–0.9)

NS

JACI 2008;121:1442–7

Number needed to treat to avoid any allergy compared to CMFPartially HF-Whey: 13 (95% CI 8 to 50)

Extensively HF-Casein: 12 (95% CI 7 to 26)

Significant risk for all allergies& atopic dermatitis (intention to treat analysis)

Cochrane-analysis: Hydrolysats vs CMF

0.4 (0.2 to 0.9)Cow’s milk allergy1 RCT (n=67)

0.8 (0.7 to 0.9)Any allergy

7 RCTs (n=2514)

RR (95% CI)Outcome

Favours hydrolysed formula 1 Favours cow’s milk formula

OsbornDA, Sinn J. Cochrane Review2006

Conclusions: formula feeding

Compared to CMF:

• Soy formula has no allergy preventive effect, not

recommended

• Certain (not all) hydrolysed formulae reduce the risk for atopic dermatitis and cow’s milk protein allergy in high risk

patients.

• Effect develops in 1st year and persists until 6 years• No effect on asthma

• No effect on allergic rhinitis

Solid food introduction and allergy

• GINI Study: 1121 high risk infants, dietary advice, weekly diaries,

f/up 1 y: no effect on AD (Schoetzau et al Ped Allergy Immunol 2002;13:234-42)

• LISA Study: 2612 unselected birth cohort, semiannual questionnaires,

f/up 2 yrs: no effect on AD of time or diversity of solid foods(Zutavern et al

Pediatrics 2006: 117:401-11)

• “Ashford” Study: 642 unselected birth cohort, annual questionnaires,

f/up 5.5 yrs: no effect on AD or wheezing of time of solid foods(Zutavern et

al ADC 2004:89:303-8)

• Preterm Study: 257 preterm infants, 4monthly questionnaires,

f/u 1y: risk factors for AD: >4 foods at 17 wks(Morgan et al ADC 2004:89:309-14)

Prospective study in 1560 children with increased risk for CD & Diabetes type 1(HLA-DQ2/8 or relatives of patients with Diabetes type 1)

1994-2004; Norris et al, JAMA 2005

1.004 – 6 months

0.97 – 3.601.87> 7v

1.44 – 18.575.171 – 3 months

95% CIHazardratioAge

Timing of introduction of gluten in childrenat risk influences the incidence of celiac disease

Timing of gluten introduction & celiac disease



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Introduction of gluten while still breast-feeding

risk for celiac disease

Akobenget al. ArchDis Child2006;91:39-43

Do we have a window of opportunity ?

Months 0 – 4 5 – 6 5 – 12

?

For countries/populations with high hygiene:

Solid foods should be introduced in the 5th and 6th

months of age, regardless of the familial risk of allergy

and breast-feeding or formula-feeding

„ Prevent CD“Prevention of Celiac Disease with Nutritional Intervention

1000 high risk infants for CD (family hx, DQ2/DQ8 pos)RCTwith gluten during months 5&6 vs. placebo)

Conclusions: Solid food introduction

• Very early solid food introduction (< 3 – 4 months of life) with a

high variety of different foods may increase the risk of

allergic diseases (eczema).

• Delaying the introduction of solids food beyond the 6th

months of life has no protective effect or may be even

increase the risk for allergy.

• This also applies to allergenic foods like hen‘s egg, cow‘smilk, fish, wheat.

Summary

● Increased incidence of allergies in countries/populations with

high hygiene (western life-style)

● Nutrition in early life plays a role for tolerance induction

● NO allergy preventive effect with maternal diet during

pregnancy and breast-feeding

● Certain hydrolysed formulae (not soy formula) reduce the risk

for atopic dermatitis & CMPA in high risk patients compared to

CMF. No effect on asthma and allergic rhinitis

● Too early (<3months) and too late (>>6 months)introduction of

solids (wheat) increases the risk for atopic dermatitis (celiac

disease) in high risk infants

● Remember: breast is best

Thank you

for your kind attention!

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Koletzko Allergy Prevention Singapore 2011

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