food allergy highlights of the past 3 years adam fox paediatric study day cheltenham june 2004 dr...

Food AllergyHighlights of the

past 3 years

Adam FoxPaediatric Study DayCheltenhamJune 2004

Dr Adam Fox

Food Allergy Research

1991-3 1994-6 1997-9 2000-2 2003-5 2006-80

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10051165 1258

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2244

‘Food Allergy’ Pub Med articles

Highlights of the past 3 years

• Prevalence of food allergy• Comorbidities• Natural History• Emerging Treatments

Highlights of the past 3 years

• Prevalence of food allergy• Comorbidities• Natural History• Emerging Treatments

Anaphylaxis epidemic?

• National database 1997-2005• 112 deaths (0.64/million)• 350% increase in food induced

anaphylaxis admissions over 11 yrs

Liew WK et al. Anaphylaxis fatalities and admissions in Australia. JACI Feb 2009;123:434-42.

• But no suchincrease in deaths

?better management

• Main increase is in 0-5 yr olds and due to peanut allergic reactions

Is peanut allergy getting out of control?

Rates of Peanut Allergic in UK Paediatric Cohorts

Venter 2005 Hourihane 2007 duToit 20080.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

1.8%

2.0%

1.0%

1.8% 1.8%

Peanut Allergy in USSicherer et al JACI 2010

1 2 30.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

0.4%

0.8%

1.4%

1997 2002 2008

Venter C et al. Time Trends in the prevalence of peanut allergy: 3 cohorts of children from the same geographical location in the UK.

Allergy 2010;65:103-8.

Born 1989 Born 1994-6 Born 2001-20

0.5

1

1.5

2

2.5

3

3.5

1.3

3.3

2

0.5

1.41.2

SensitisedAllergic

n=2181 n=1273 n=891

Pre-COT Post-COT

..and it isn’t just here

Ben-Shoshan M et al, JACI Apr 2009

2000-2002 2005-20070.00%

0.20%

0.40%

0.60%

0.80%

1.00%

1.20%

1.40%

1.60%

1.80%

1.34%

1.62%

Highlights of the past 3 years

• Prevalence of food allergy• Comorbidities• Natural History• Emerging Treatments

Food Allergy & Eczema – beyond reasonable doubt

What we knew:• Link between AE & likelihood of FA• Link between increasing severity of AE &

likelihood of FA

Hill DJ et al. PAI 2004;15:421-7. Hill DJ et al. J Pediatr 2000;137:475-9.Hill DJ et al. J Pediatr 2007;151:359-63.

0

10

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70%

wit

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A a

t 12 m

on

ths

0 1 2 3 4

Group

Food Allergy increases with AD severity

Hill D, Hosking C. Food Allergy and Atopic Dermatitis in infancy. Paed Allergy Immunol 2004;15:421-7.

Food Allergy & Eczema – beyond reasonable doubt

What we knew:• Link between AE & likelihood of FA• Link between increasing severity of AE & likelihood of

FA

What we needed to know:• Is this reproducible in a large cohort, international

study• Are there other important factors to predict likelihood

of FAHill DJ et al. PAI 2004;15:421-7. Hill DJ et al. J Pediatr 2000;137:475-9.Hill DJ et al. J Pediatr 2007;151:359-63.

Hill DJ et al. Confirmation of the Association between high levels of IgE food sensitisation & eczema in infancy:

an international study. Clin Exp Allergy;38:161-8.

• 2222 children from 94 centres in 12 countries (mean 17months) with AE and allergic FHx

• SCORAD for eczema severity• SpIgE to egg, milk and peanut• Used previously validated ‘decision points’

based on 90% PPV to define HR-IgE-FS

Relationship between eczema & HR-IgE-FS

Limitations

• No DBPCFC but....• Used validated cut offs• High specificity of cut offs means many true

food allergics would have been missed• Probably underestimating food allergy as only

3 allergens tested.

Summary

• In infants with AE, the earlier the age of onset and the more severe the eczema, the more likely there is to be food allergy

Clinical Implication:• Food allergies should be routinely assessed for

in infants with moderate or severe eczema

Highlights of the past 3 years

• Prevalence of food allergy• Comorbidities• Natural History• Emerging Treatments

Outgrowing Food Allergy

What we knew:• Upto 75% of IgE mediated milk allergy is outgrown by 3

years•Danneus A et al 1981, Host A et al Allergy 1990, Bishop J et al J Paediatr 1990

• Tolerance is unlikely if not obtained by school age– Hill DJ et al CEA 1993, Saarinen KM et al JACI 2005

• SPT/SpIgE wheal size relates to likelihood of clinical allergy

What we needed to know:• Is this reproducible in a larger, more recent studies• What predicts tolerance?

Skripak JM et al. The Natural History of IgE mediated Cow’s Milk Allergy. JACI;120:1172-77.

• Retrospective review of over 1000 IgE mediated milk allergic patients seen by author over 15 years

• Clinical history, test results and outcome collected on 807 patients

• Patients considered tolerant after they passed a challenge or experienced no reactions in the past 12 months and had a cow’s milk IgE <3 kU/L.

Natural History of IgE mediated milk allergy

81

58

36

21

0

10

20

30

40

50

60

70

80

90

<4 yrs <8 yrs <12 yrs <16 yrs

Resolution of CMPA n=807

% allergic to CMP

Skripak JM et al. The Natural History of IgE mediated Cow’s Milk Allergy. JACI Nov 2007.

Limitations

• Skewed tertiary care population• Possible underestimation of tolerance

– Lost to follow up probably more likely to be tolerant

– Some not challenged due to high SPT/SpIgE may have outgrown

• Patients with persistent CMPA had higher IgE levels in first 2 years of life

• The higher the peak IgE level, the lower the chance of tolerance

• Similar for egg

Savage J et al. The Natural History of egg Allergy. JACI 2007Benhamou et al. PAI 2008.

Can Allergy Tests Predict Outgrowing?

Clinical Implication:

• Tolerance may be taking longer than expected but may still develop in adolescence – don’t stop following them up

• Initial allergy test results should be considered when counselling parents regarding prognosis

• Is milk allergy becoming a more persistent disease?

Highlights of the past 3 years

• Prevalence of food allergy• Comorbidities• Natural History• Emerging Treatments

Managing Food Allergy - MilkWhat we knew:• Allergen avoidance is the optimal management strategy• Children who outgrew milk allergy had milk-specific IgE antibodies

primarily directed against conformational epitopes.• Children with persistent milk allergy also had IgE antibodies

directed against specific sequential epitopes.

Chatchatee P et al. CEA 2001;31:1256-62. Chatchatee P et al. JACI 2001;107:379-83.Jarvinen KM et al. JACI 2002;110:293-7. Vila L et al. CEA 2001;31:1599-606.

Jarvinen K-M et al. Allergy 2007

Linear/sequential Conformational

Managing Food Allergy - MilkWhat we knew:• Allergen avoidance is the optimal management strategy• Children who outgrew milk allergy had milk-specific IgE antibodies

primarily directed against conformational epitopes.• Children with persistent milk allergy also had IgE antibodies

directed against specific sequential epitopes. What we needed to know:• Can those with IgE to conformational epitopes tolerate cooked

milk? – do they represent a milder phenotype & if so, how can we identify them?

• Will regular allergen exposure impact on tolerance?• In other words.....

Chatchatee P et al. CEA 2001;31:1256-62. Chatchatee P et al. JACI 2001;107:379-83.Jarvinen KM et al. JACI 2002;110:293-7. Vila L et al. CEA 2001;31:1599-606.

All mild

Are we being too strict?

• After 3 months of HM – no effect on growth or intestinal permeability• HM tolerant had smaller SPT & lower bLG/Casein SpIgE• None with SPT<5 reacted to HM. 5kU was 90% cut off for reacting

Nowak-Wegrzyn A et al. JACI, August 2008

100 Milk allergic children (2-17 yrs) with +ve allergy tests

Summary:

• 2 different phenotypes in IgE mediated milk allergy• Mild – tolerate baked milk, milder reactions, smaller

test and outgrow earlier• Severe – don’t tolerate baked milk, severe

reactions, larger test and outgrow later

Clinical Implications:• When do I start challenging....?

Impact on tolerance development?Kim et al JACI 2011

• 3 groups– Heated milk tolerant (mild phenotype)

– Heated milk reactive (severe phenotype)

– Comparison Group (retrospective age/sex/IgE matched controls who had ‘standard care’)

HM tolerant vs HM reactive

80% vs 24% tolerant of unheated milk over 5 years

HM tolerant vs comparison group

80% vs 33% tolerant of unheated milk over 5 years

Conclusions

• Baked milk, if tolerated, is safe convenient and well accepted

• Appears to enhance development of tolerance but prospective controlled study still to be done

Oral tolerance induction to peanut

• 4 confirmed peanut allergics• Gradually increased doses of oral peanut • 2 weekly supervised increments to 800mg• All tolerated at least 10 peanuts at challenge• 18 more patients successfully treated• RCTs to follow....• ? Long term effect and ?safety

Clarke A et al. Allergy 2009.

Desensitisation vs Tolerance

• Desensitisation – a change is threshold of allergen required to cause allergic symptoms

• Tolerance – induction of long term immunologic changes associated with the ability to ingest allergen without symptoms or ongoing therapy

Blumchen et al. Oral peanut Immunotherapy in children with peanut

anaphylaxis, JACI 2010• 23 kids

aged 3-14

• Unstable asthma excluded

Results• Only 5/23 achieved 500mg dose on rush

protocol . 1 too anxious to complete.• 5 who achieved 500mg with rush had

significantly lower peanut SpIgE than others• Long term build up more successful – 14

reached 500mg dose• Mean 4 fold increase in dose tolerated at final

OFC, compared to initial OFC• 3 patients tolerated less than their

maintenance at final OFC whilst 3 tolerated 4g top dose

Results

• 4 patients withdrawn due to SE• All worsening of pre-existing asthma• No adrenaline used (but trained to use

salbutamol first for moderate respiratory symptoms

• 0.9% of doses required salbutamol• Peanut specific downregulation of IL2, IL4 &

IL5 (but no increase in IL10) and increased IgG4

Implications

• Rush protocol does not seem suitable (except possibly for those with low SpIgE)

• Long term build up seems to be safe and effective at reaching clinically relevant thresholds

• Possible early evidence of long term tolerance induction