Why does Australia have the highest rates of Food Allergy?

Professor Katie Allen

Why does Australia have the highest rates of Food Allergy? Update on Healthnuts

The HealthNuts Study A population based cohort study in Melbourne Australia of 5300 infants followed from age 1-10 years

The HealthNuts Study 1)

Population sample – 73% participation 2) SPT (peanut, egg, cow’s milk and sesame)

and questionnaire (n=5276) at age 1yo Non-participant questionnaire

3) Oral Food Challenge for all sensitised children (n=1089) and 200 negative controls

4) Follow up at age 2,4,6 and 10 years

Koplin J et al, Cohort Profile, IJE 2016

More than 20% with food sensitisation

egg: peanut: cows milk:

16% 9% 6%

TOTAL:

>20%

Osborne et al. JACI 2011; 127: 668-678

Over 10% had challenge-proven food allergy • egg: • peanut: • other: TOTAL:

9% 3% 2% >10%

Osborne et al. JACI 2011; 127: 668-678 Predetermined stopping criteria for food oral food challenges (Koplin et al JACI 2011)

One or more of following: 1)>3 non contact concurrent urticaria lasting more than 5 min 2) angioedema 3) vomiting 4) Anaphyaxis

Why is the prevalence of food allergy so high in Australia?

Is this region different to elsewhere?

Genes or environment or both?

Epidemiologic considerations • Allergy has arisen more quickly than genes can change • Is it something to do with the developed country lifestyle? – Presumably mediated by epigenetic regulation of gene control

Prevalence 1950

1970

1990

2010

Current leading hypotheses of postnatal modifiable factors for the rise in food allergy 1. Skin barrier function and infant feeding - the “Dual Allergen Exposure� or Lack hypothesis

2. Vitamin D hypothesis 3. Hygiene hypothesis (microbial diversity, migration and the modern lifestyle)

Current leading hypotheses of postnatal modifiable factors for the rise in food allergy – 5 Ds 1. Hygiene hypothesis (microbial diversity, migration and the modern lifestyle) – Dogs and Dirt 2. Vitamin D hypothesis 3. Skin barrier function and infant feeding - Dry skin and Diet - the “Dual Allergen Exposure” or Lack hypothesis Allen & Koplin J Allergy Clin Immunol in Practice 2016

Current leading hypotheses for the rise in food allergy 1. Skin barrier function and infant feeding (the “Dual Allergen� or Lack hypothesis) 2. Vitamin D hypothesis 3. Hygiene hypothesis (microbial diversity, migration and the modern lifestyle)

Dual Allergen Exposure (or Lack) Hypothesis

(Gideon Lack 2008)

Earlier onset and more severe eczema more likely to develop food allergy 80% Eczema treatment Strong topical corticosteroid

60%

Mild topical corticosteroid Moisturizers only No moisturizers or steroids

40%

20%

0% Birth-3 months

4-6 months

7-9 months

10-12 months

Age of diagnosis

Martin PJ et al CEA 2014

Ranked prevalence plots of current symptoms of eczema for the age group 6 to 7 years

Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three Odhiambo et al JACI 2009

Filaggrin: filament-aggregating protein • key role: epidermal differentiation & skin barrier function Hygroscopic amino acids

Filaggrin proteins aggregate & align keratin filaments cleaved

Profilaggrin (in keratohyalin granules)

Immunohistochemical staining for filaggrin

epidermal barrier to prevent water loss and allergen penetration

Cornified cell envelope ďƒ mechanical strength

FLG loss-of-function mutations increase the risk of food sensitization but do not play a further role in progression of food sensitization to food allergy in one-year-old infants.

These results suggest a biologically plausible role for FLG in the development of food sensitization but additional as yet undetermined factors are required to direct the immune response towards food tolerance or allergy in early life.

Tan et al JACI 2012

Current leading hypotheses for the rise in food allergy 1. Skin barrier function and infant feeding (the “Dual Allergen� or Lack hypothesis) 2. Vitamin D hypothesis 3. Hygiene hypothesis (microbial diversity, migration and the modern lifestyle)

Potential explanation for rise in prevalence • Changes in timing of exposure to allergenic foods: Progressive delay in timing of first exposure to solid foods • 1960s: Average age 2 months Harris LE, Chan JC. Am J Dis Child 1969;117(4):483-92.

• 1970s: Guidelines recommended delay until after 4 months Challacombe DN. Arch Dis Child 1983;58(5):326.

• 1990s: Guidelines recommended delay until after 6 months Grimshaw KE, Allen KJ et al. Allergy 2009;64(10):1407-16.

• 2000s: Guidelines recommended delay allergenic foods until after 1 year of age (up to 3 years for peanuts) American Academy of Pediatrics. Pediatrics 2000;106:346-9.

Koplin et al, JACI 2010

Infants introducing cooked egg 4-6 mth were 5 times less likely to develop egg allergy than if introduced after 10 months Adjusted*

Unadjusted N

% allergic

OR (95% CI)

P

OR (95% CI)

P

Cooked egg given first†4-6 months

150

2.0

1.0

0.002

1.0

7-9 months

398

8.3

4.4 (1.3-14.7)

4.4 (1.3-15.1)

10-12 months

348

10.9

6.0 (1.8-19.8)

5.4 (1.6-18.3)

4-6 months

311

7.6

1.0

7-9 months

499

8.2

1.1 (0.7-1.8)

0.9 (0.5-1.7)

10-12 months

361

9.7

1.3 (0.8-2.2)

1.0 (0.5-1.9)

0.009

Baked egg given first‥ 0.58

1.0

Koplin J et al JACI 2010

0.99

The LEAP trial: High risk cohort = early onset eczema and/or egg allergy

86% Relative Reduction

70% Relative Reduction

81% Relative Reduction

Population responses to change in infant feeding guidelines in Australia Tey D et al JACI 2014

Solids introduction between 4-6 months 91.7% (95%CI [90.9-92.5])

Peanut introduction >12 months 71.6% (95%CI [70.3-72.8])

Egg introduction between 7-12 months 70.6% (95%CI [69.4-71.9])

Tey D et al JACI 2014

Preliminary analysis suggests that the change in population behaviour towards infant feeding has not affected food allergy prevalence in Australia

HealthNuts

Koplin et al JACI 2016

Current leading hypotheses for the rise in food allergy 1. Skin barrier function and allergen exposure (the “Dual Allergen� or Lack hypothesis) 2. Vitamin D hypothesis 3. Hygiene hypothesis (microbial diversity, migration and the modern lifestyle)

The Longitudinal Study of Australian Children

(n=10,000)

Osborne NJ et al. JACI, 2012

Infants with Vitamin D insufficiency at 12 months are much more likely to have food allergy – but effect not seen in Asian infants

Allen KJ et al JACI 2013

JACI 2016

Is the timing of rise in food allergy consistent with Vitamin D insufficiency rising?

JACI 2013

Vitamin D insufficiency is rising in Australia • High rates in Australia – 40% of Australian pregnant women develop low vitamin D » (Morley MJA 2009, Teale 2010) • Australia (unlike the Northern Hemisphere) • does not recommend routine Vitamin D infant supplementation • has no vitamin D fortification of the food chain (with the exception of margarine).

• Anti skin cancer campaigns initiated in the 1970s have been highly successful (slip, slop, slap, wrap) in Australia

BMJ Open. 2015

VITALITY trial: protocol for a randomised controlled trial to establish the role of postnatal vitamin D supplementation in infant immune health.

Allen KJ1, Panjari M2, Koplin JJ3, Ponsonby AL3, Vuillermin P2, Gurrin LC4, Greaves R5, Carvalho N6, Dalziel K6, Tang ML3, Lee KJ7, Wake M3, Curtis N3,Dharmage SC8.

• • • •

N=3000 infants at 2mth recruitment Randomised to 400IU Vitamin D vs placebo Breastfed infants, daily drops 2 to 12 mth Outcomes: Challenge proven food allergy

Current leading hypotheses for the rise in food allergy 1. Skin barrier function and allergen exposure (the “Dual Allergen� or Lack hypothesis) 2. Vitamin D hypothesis 3. Hygiene hypothesis (microbial diversity, migration and the modern lifestyle)

Microbial diversity Contact with pets and siblings

Infants with siblings and dogs at home are much less likely to develop food allergy

Allergy 2012

Migration a “natural experiment� in environmental change

Prevalence of food allergy stratified by parent's country of birth 30%

Allergy 2014 20%

10%

0

Both Aust

One Europe

Both Europe

Any food allergy N=408 Peanut allergy N=370 Milk allergy N=23

One Asia

Both Asia

Egg allergy N=370 Sesame allergy N=22

Infants of parent’s born overseas were much more likely to have food allergy but risk of allergy amongst parents was reversed Koplin JJ et al, Allergy 2014

‌.but what about children born in Asia who migrated to Australia – were they protected?

Modifiable lifestyle risk factors that could explain the rise in food allergy risk in offspring of Asian migrants in Australia Asia Low rates of infantile eczema High ambient humidity ?Less soap use

Higher genetic risk AND Change in environment with migration

Higher rates of food allergy in Asian migrant offspring born in Australia Asia Non-Westernised diet Eg boiled vs roasted peanut Higher fruit and veg ?different infant feeding patterns

Allen & Koplin Pediatric Clinics of North America 2015

Asia Diverse microbe exposure Larger families/more crowding More exposure to animals Less clean food and water supply Higher rates of H pylori and parasites Less antibiotics in personal health and food chain Lower rates of Caesarean section

Asia Less Vit D deficiency or Vit D binding protective SNPs Closer to equator – increased UVR exposure ?Less sun avoidance

Phenotypes of Early-life Allergic Disease

Phenotypes of allergy 1

No allergic disease (70%) 0.8

Non-food sensitised eczema (16%)

0.6

Single egg allergy (9%) 0.4

Multiple food allergies (predominantly peanut) (3%)

0.2

Multiple food allergies (predominantly egg) (2%)

0 Egg sensitised

Egg allergy

Peanut sensitised

Peanut allergy

Sesame sensitised

Sesame allergy

Early-onset Late-onset eczema eczema

Wheeze

Food Allergy Phenotypes

Single egg allergy: Siblings, FLG Vitamin D

• •

Identified 5 phenotypes of allergic disease in infancy Shared and individual risk factors suggesting that drivers for the development of allergic disease may differ by phenotype

Shared risk factors: Non-sensitised eczema: Siblings, FLG Bronchiolitis, colic

FHx allergy

Parent’s country of birth Age introduction to egg Males Pet dogs

Multiple FA (peanut): Pre-term birth Vitamin D

Multiple FA (egg): Breastfeeding Vitamin D

Healthnuts Publications 2016 in press/under review • Partially hydrolysed formula does not prevent allergic disease – Goldsmith et al JPCH 2016 • GWAS supports HLA assoc– Martino et al CEA (revisions requested) • SPINK5 is associated with food allergy – Ashley et al Allergy (revisions requested) • IL13 is associated with food allergy – Ashley et al (submitted PAI) • Environmental factors explain difference in prevalence between Healthnuts and BIS – Molloy et al (submitted JACI) • Persistent and resolved food allergy increases the risk of asthma age 4yo – Vermeulen et al (submitted JACI) • Angioedema is more common than urticaria in age 4yo food challenges compared to age 1yo – Ho et al (submitted JACI in practice) • Prevalence of allergic disease at age 4yo – Peters et al (submitted CEA) • Egg component resolved diagnostics predict resolution but not allergy – Dang et al (submitted JACI in practice) • Prevalence of tree nut allergy –McWilliams et al (submitted JACI)

Acknowledgements HealthNuts Investigators • Chief Investigators: Katie Allen (PI), Melissa Wake, Shyamali Dharmage, Mimi Tang, Lyle Gurrin, Melanie Matheson, Terry Dwyer, Colin Robinson • Associate Investigators: Anne-Louise Ponsonby, David Hill, Adrian Lowe Postdoctoral Fellows • Jennifer Koplin, David Martino, Thanh Dang, Nick Osborne Students • Pamela Martin, Tina Tan, Rachel Peters, John Zurzolo, Noor Suaini, Anna Nicolaou, Sonia Chabdra, Kate Nicholls Research Team (past and present) • Leone Thiele, Helen Czech, Holly Shaw, Deborah Anderson, Hayley Crawford, Megan Mathers, Olivia Hamilton, Kaye Trembath, Lucy Miles, Marg Sutherland, Margie Gibson, Marjolein Slaa, Kirsten Aurich, Jeeva Sanjeevan, Rachel Keogh Research Fellows • Marnie Robinson, Dean Tey, Mark Nethercote, John Molloy Funding • NH&MRC of Australia, US Department of Defence (for GWAS), Ilhan Food Allergy Foundation, AnaphylaxiStop, Australian egg corporation (age 2 follow up)

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Thank you for your attention!

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