Preventing allergy by nutritional intervention

Sibylle Koletzko

Objectives

Epidemiology of allergy and the hygiene hypothesis Possible allergy prevention by nutritional intervention

Dr. von Haunersches Kinderspital, Ludwig-MaximiliansUniversity Munich

Maternal diet during pregnancy and breast-feeding Breast-feeding Soy formula Hydrolysed formula (the GINI-study) Supplementary feeding

The prevalence of the different allergic diseases in relation to age

allergic rhinitis
Prevalence

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

atopic dermatitis asthma food allergy

15
von Mutius

Age (years)

Atopy and exercise-induced bronchospasm in Ghana: 1993-2003

16
P<0.001

14 12 10 % 8 6 4 2 0 Atopy EIB
EOD Addo Yobo & A Custovic, 2006 P=0.004

1993 2003

Atopy and exercise-induced bronchospasm amongst urban rich, urban poor and rural children in Ghana in 1993
12 10 8 6 4 2 0 Urban Rich Urban poor Rural Atopy EIB %

Infections and chronic inflammatory disease

Crohns disease Rheumatic fever Hepatitis A Multiple sclerosis

Tuberculosis Mumps Measles Asthma Type 1 diabetes

EOD Addo Yobo & A Custovic, Thorax 1997

J. F. Bach, NEJM 2002

Hygiene Hypothesis
Improved hygienic conditions Less microbial exposure during early childhood Slower post-natal maturation of the immune system Delayed development of the optimal balance between TH-1 and TH-2-like immune response
Stachan, BMJ 1989

Factors influencing the gut flora

Genes, receptors Mode of delivery Fibres, prebiotics

Gut flora
Maternal gut flora Age Bacteria, probiotics

Type of food, breast feeding Antibiotics, drugs

Developmental deviations of Th-cell cytokine profiles in infants indicating future atopic sensitization and allergy
Th2:Th1 ratio Relative T-cell memory response patterns Window for fine-tuning Atopic disease Sensitization (IgE antibodies) Tolerance Healthy child 24 Age months Atopic child

Possible nutritional approaches for primary prevention

WHEN: Prenatal postnatal?

To WHOM: Maternal diet during pregnancy and lactation? Nutritional intervention in infant? All infants? High risk infants? Elimination or supplementation?

Birth 3

12

18

HOW:

Based on data from Patrick G. Holt and coworkers, Perth, Western Australia (Clin. Exp. Allergy. 1998; 28 Suppl. 5: 39-44, Lancet 1999; 353: 196-200)

Who is at high risk for allergy?

Risk depends on family history

Critical review on nutritional measure for prevention of allergy

Parental allergy

Risk for offspring

Epidemiological data Observational studies Interventional studies To assess a cause-effect-relationship, only prospective interventional studies are appropriate (no retrospective, no cross-sectional, no prospective non-interventional)

None 1 with allergic disease 2 with allergic disease 2, same manifestation 2 parents + 1 sibling

5% 20 % 40 % 75 % 85 %
Kiellman, JACI 1999

Possible nutritional approaches for primary prevention

Maternal exclusion diet during pregnancy and lactation Breastfeeding Delayed introduction of solid foods to infant Soy or hypoallergenic infant formula Supplementary feeding

Maternal diet during pregnancy

Outcome measure
Atopic eczema in first 12-18 months (2 RCTs, n=334) Asthma in first 18 months (2 RCTs, n=334) Allergic urticaria in first 18 months (1 RCT, n=163) Any atopic condition in first 18 mon. (1 RCT, n=163)
Favours elimination diet 1

RR (95% CI)
1.01 (0.6-1.8) 2.2 (0.4-13)

1.01 (0.20-5.15) 0.71 (0.34-1.49)

Favours regular diet

Kramer, Kakuma. Cochrane Review 2006

Maternal diet during breast-feeding

Outcome measure
Atopic eczema in first 18 mo (1 RCT, n=26)
1

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)
ESPGHAN 1999, 2008 American Academy of Pediatrics (AAP) 2008 Deutsche Ges Kinder- und Jugendmedizin 2008 Leitlinien Allergieprvention 2009

RR (95% CI)
0.7 (0.3-1.7)

Outcome measure
Eczema area score (1 RCT, n=34) Eczema activity score (1 RCT, n=34)
Favours elimination diet 1

WMD (95% CI)

-0.8 (-4.4 to 2.8) -1.4 (-7 to 4.4)

Favours regular diet

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 asthma

US Agency for Healthcare Research and Quality, 2007

??

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.

Exclusive breast-feeding for at least 3 months does NOT reduce the risk for later atopic dermatitis

Formulae for infants

For treatment of cows milk allergy

Soy formula: no benefit for allergy prevention

Intact Protein

Partially hydrolyzed

Extensively hydrolyzed

Amino acid formula

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

Cows milk formula Soy formula Goats milk formula

HA-formula Whey Casein

Whey Casein

Allergenicity

Hypoallergenic protein hydrolysates

Depending on the degree of enzymatic hydrolysis, ultraheating and ultrafiltration classified as partially hydrolysed formula (pHF) and depending on the protein source whey or casein hydrolysate
(18% >6000 Dalton)

Hydrolysed formulae: Major questions

Are hydrolysed cows milk based formulae able to reduce the incidence of allergic diseases? Short- or long-term effect? Is the starting protein (whey/casein) and/ or the degree of 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?

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

German Infant Nutritional Intervention study

Recruitment and study design

5991 healthy term neonates born 1995-1998

Objective of the study

To investigate the allergy preventive effect of three different hydrolysed formulas compared with a regular cows 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 Ministry for Education, Science, Research and Technology, grant no 01 EE 9401-4

Pos. family history of allergy

Pos. family history, but refusal Neg. family history of allergy

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

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

Formula used for intervention

Feeding recommendations in the intervention 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 cows milk and diary products, henss egg, fish, nuts, and citrus during the first year of life.

Hydrolysates: Partially hydrolysed whey formula pHF-W NAN HA Extensively hydrolysed whey formula eHF-W Nutrilon pepti Extensively hydrolysed casein formula eHF-C Nutramigen compared with Regular cows milk based formula CMF
Blinded formulas of the GINI study, 4 letters for each kind of formula

Feeding characteristics in intervention group: Distribution of study formula and human milk
n= 1810 %

Adjusted cumulative incidence of physician diagnosed atopic dermatitis in fully breast-fed infants with positive and negative family history of atopy

100 80 60 40 20 0 CMF n=453 pHF-W n=455 eHF-W n=456 eHF-C n=446

excl. study formula

study formula + human milk

excl. human milk

Non-intervention, pos. family history Non-intervention, neg. family history HR 1.9 (95% CI 1.5-2.4) Intervention, pos. family history

v. Berg et al. Clin & Experimental Allergy 2009

Significant different characteristics between fully breastfed & partly or non-breastfed children in the intervention & non-intervention group
80 70 60 50 40 30 20 10

Cumulative incidence of atopic dermatitis in the 4 intervention groups (per protocol analysis)
%
25 20
CMF eHF-W pHF-W eHF-C

* p<0.05

* * * * * * * * *

15 10
* *

* * * *

* *

0
an rb U

5 0
birth first second third year
*p < 0.05 for pHF-W and eHF-C vs CMF

ea ar

y 10 l> oo ch S

g g n in ki o ep sm ke al et n P er at M

s id ol S

4 <

on m

M P ,C gg E

fully BF Int

mixed/no BF Int

fully BF Non-Int

mixed/no BF Non-Int

J Pediatr 2004;104:602-7

v. Berg, Koletzko et al. JACI 2003;111:533-40

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

Adjusted cum. Incidenz von Arztdiagnose

40 35 30 25 20

Adj. cumulative incidence of physician diagnosed atopic dermatitis Adjusted infants with pos. and neg. family in formula-fedcum. Incidenz von Arztdiagnose history for atopy
NI = non-intervention, formula freely chosen by mother
physician diagnosed eczema [adj. %] 40 35 30 25 20 15
N=402 N=118 N=224

NI = non-intervention, formula freely chosen by mother

physician diagnosed eczema [adj. %]

I: noncompliant I: CMF NI:

NI:

NI pos. family history

Pos. familiy history

NI:

Neg. family history

NI:

15
N=402

NI neg. family history

10 9 8 7 6 0

10 9 8 7 6 0

N=889

N=889

2 3 age [years]

2 3 age [years]

NI FH+, HR 2.1 (95% CI 1.6-2.7) I non compliant, HR 2.7 (95% CI 1.9-3.9) I CMF, HR 2.6 (95% CI 2.0-3.5)
I =Intervention v. Berg et al. Clin & Experimental Allergy 2009

NI pos. family history NI neg. family history HR 2.1 (95% CI 1.6-2.7)

NI FH-,
NI non-Intervention v. Berg et al. Clin & Experimental Allergy 2009

Adj.Adjusted cum. Incidenz von Arztdiagnose cumulative incidence of physician diagnosed atopic dermatitis in formula-fed infants with pos. and neg. family history for atopy
physician diagnosed eczema [adj. %] 40 35 30 25 20 15
N=118 N=224 N=211 N=402

I: noncompliant I: CMF NI: I: eHF-W I: pHF-W I: eHF-C

Significant risk for all allergies & atopic dermatitis (intention to treat analysis)
Comparison vs CMF Part. Hydrol. Whey Ext. Hydrol. Whey Ext. Hydrol. Casein All allergies Atop. dermatitis Asthma & allergic rhinitis NS NS NS

Pos. familiy history

NI:

Neg. family history

0.8
(0.70.96)

0.8
(0.70.97)

10 9 8 7 6 0

N=204 N=180

NS

NS

N=889

0.8
(0.70.9)

0.7
(0.60.9)

2 3 age [years]

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) I =Intervention

NI FH+ fb-, HR 2.1 (95% CI 1.6-2.7) NI FH- fb-, 1.0 NI = non-Intervention

v. Berg et al. Clin & Experimental Allergy 2009

Number needed to treat to avoid any allergy compared to CMF

Partially HF-Whey: 13 (95% CI 8 to 50) Extensively HF-Casein: 12 (95% CI 7 to 26)
JACI 2008;121:14427

Cochrane-analysis: Hydrolysats vs CMF

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 cows 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

Outcome Any allergy 7 RCTs (n=2514) Cows milk allergy 1 RCT (n=67)
Favours hydrolysed formula 1

RR (95% CI) 0.8 (0.7 to 0.9) 0.4 (0.2 to 0.9)

Favours cows milk formula Osborn DA, Sinn J. Cochrane Review 2006

Solid food introduction and allergy

Timing of gluten introduction & celiac disease

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

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)

Age 1 3 months 4 6 months > 7v

Hazard ratio 5.17 1.00 1.87

95% CI 1.44 18.57

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)

0.97 3.60

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)

1994-2004; Norris et al, JAMA 2005

Timing of introduction of gluten in children at risk influences the incidence of celiac disease

Introduction of gluten while still breast-feeding risk for celiac disease

Do we have a window of opportunity ?

?
Months 0 4 56 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
Akobeng et al. Arch Dis Child 2006;91:39-43

Prevention of Celiac Disease with Nutritional Intervention

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

Prevent CD

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 hens egg, cows milk, 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

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