Bret Haymore, MD FAAAAI, FACAAI

Food Oral Desensitization: Potential & Pitfalls

OBJECTIVES

- Understand prevalence and evaluation of patients

with suspected food allergy

- Understand management of food allergy

- Understand role of food desensitization in

management of food allergy

DISCLOSURES

NONE

Background: Food Allergy

• Prevalence:–

–

3 million school age children (3.9%)

18% increase since 1997Branum 2009 Pediatrics. 124:1549-55

• 7 most common food allergens in U.S.– Milk, egg, peanut, tree nuts, shellfish, soy, wheat

• Peanut allergy

• Standard of care–

–

Avoidance of only foods appropriately diagnosed

Self-injectable epinephrine/antihistamines

Vander Leek, J Peds 2000

Bock, J Allergy Clin Immunol 2007

- Prevalence ~1%- Most common cause of anaphylaxis in children

presenting to ED- Most common cause of fatal food anaphylaxis

Background: Food Allergy

• Accidental exposures–

––

Incidence ~33% per year

Peanut IgE can’t predict severityVast majority of fatalities in patients with known allergy

•

– Generally by school age

• Significant adverse effect on quality of life– Greater than some other chronic diseases (i.e., type 1 diabetes)

Cummings 2010 Allergy 65(8):933-945

• No proactive therapy available

Fleischer 2007 Curr.Allergy Asthma Rep. 7:175-181Skripak 2007 J Allergy Clin.Immunol. 120:1172-1177

~20% of Children with peanut allergy outgrow the disease

Peanut Sensitization

Burks AW. Lancet 2008;371,9623:1538-1546

Peanut Sensitization

Burks AW. Lancet 2008;371,9623:1538-1546

Development of Treatment Options

• Chinese herbal medicine – in trials now

Li, X 2003 J.Allergy Clin.Immunol. 112:159-167

• Allergen-specific

•

••

Engineered recombinant protein – reduced

Oral immunotherapy (OIT) Sublingual immunotherapy (SLIT)

IgE binding

Skripak Current Opinion In Immunology 2008,20:690-696

• Allergen non-specific

• Anti-IgE – not stand alone treatment Leung, Sampson, et al. NEJM 2003; 348:986-93

Initial Food Allergy Study Goals

• Goals of treatment are two-fold

– Clinical desensitization• tolerate more food before an accidental reaction

– Eventual clinical tolerance• off treatment

• Goals of research on food allergy treatment

– Identify immunologic markers associated with the treatment

• Identify the mechanisms of the changes brought on by the treatment

Methods of Immunotherapy

• Oral IT (OIT)– swallowed with food

• Sublingual IT (SLIT)– sublingually then swallowed

• Differences– amount of protein, route?, digestion?,

possibility of causing tolerance?

OIT SLIT

Peanut OIT Blinded Study Design

4000 mg

Jones et al. AAAAI 2010‐

1 peanut = 300 mg

Initial escalation day – 6 mgDesensitization

Food Challenge #1(OFC 1)

Dose Escalation

Maintenance

Peanut OIT Blinded Study Design

Off OIT

1 mo

Jones et al. AAAAI 2010‐

1 peanut = 300 mg

Tolerance

4000 mg

Initial escalation day – 6 mgDesensitization

Food Challenge #1(OFC 1)

Dose Escalation

Maintenance

Meet criteria for assessing tolerance

Food Challenge #3 (OFC3)

Food Challenge #2 (OFC 2)

Peanut OIT – Blinded Study

•25 subjects – 16 - active treatment; 9 - placebo

•Any peanut-allergic subject – unless accompanied by significant hypotension

•All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up

*

*

P=.008*

Jones et al. -AAAAI 2010

Peanut OIT – Blinded Study

•25 subjects – 16 - active treatment; 9 - placebo

•Any peanut-allergic subject – unless accompanied by significant hypotension

•All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up

**

*

*

P=.008 P=.001* *

Jones et al. -AAAAI 2010

Serum Levels of Peanut-Specific IgE and IgG4

Change withTreatment

Jones et al. -AAAAI 2010

ImmunoCAP-FEIA (Phadia)

Serum Levels of Peanut-Specific IgE and IgG4

Change withTreatment

Jones et al. -AAAAI 2010

ImmunoCAP-FEIA (Phadia)

Peanut OIT

Allergen-Specific T cells

• Basophil markers - %CD63

– Significant change over first few months of

OIT

• Peanut-specific CD4+CD25+Foxp3+

– T-Regulatory cells

T cells

•

•

increased at 12 months

decreased thereafter

• Peanut-specific cytokines

– Decreased – pro-allergic cytokines - IL-4, IL-5, IL-13– Increased – regulatory cytokines - IL-10, TGF-ß Breslin et al. AAAAI - 2010

Jones, Burks et al. – J Allergy Clin Immunol – August 2009

Permanent Tolerance Develops

3 Years of OIT

after

• 27 subjects - on OIT >36 months

• 13/27 (48%) passed food challenges

• Off treatment• These subjects remain off OIT and ingest peanut in their diet

to peanuts

Varshney, Jones, Burks et al. AAAAI 2010

Methods of Immunotherapy

• Oral IT (OIT)– swallowed with food

• Sublingual IT (SLIT)– sublingually then swallowed

• Differences– amount of protein, route?, digestion?,

possibility of causing tolerance?

OIT SLIT

Sublingual Immunotherapy (SLIT)

5%(1) Initial pilot study (Duke)

- Adolescents and adultsLaubach, Burks, et al. J Allergy Clin Immunol 2008;121:S96Bird et al. J Allergy Clin Immunol 2009

Total home

4%

3%

2%

1%(3) 3rd study (CoFAR-NIH)

0%

Skin Upper Resp Chest Abdomen

- Adolescents and adults –

3 year study

Symptom

per

cen

t o

f h

om

e d

ose

s

4.6%

doses(n=4737)

0.6%

oropharyngeal

non-oropharyngeal 0.7%

0%

• SLIT – Peanut allergic adults and children

(2) 2nd blinded study (Duke) – children Bird et al. AAAAI 2010, Kim et al. AAAAI 2010

SLIT Causes Clinical and Mast Cell Desensitization

• Peanut extract – given sublingually•

••

8 gtts (2 mg) maintenance dose

Updosing period – 6 months; Maintenance dosing – 6 monthsDouble-blind, placebo-controlled food challenge (DBPCFC) at 12 monthsDBPCFC

• SLIT – peanut allergic children and adults 2nd blinded study (Duke) – children Bird et al. AAAAI 2010, Kim et al. AAAAI 2010

• Peanut extract – given sublingually•

••

8 gtts (2 mg) maintenance dose

Updosing period – 6 months; Maintenance dosing – 6 monthsDouble-blind, placebo-controlled food challenge (DBPCFC) at 12 months

DBPCFC Peanut prick skin test

SLIT Causes Clinical and Mast Cell Desensitization

• SLIT – peanut allergic children and adults 2nd blinded study (Duke) – children Bird et al. AAAAI 2010, Kim et al. AAAAI 2010

– then

Johns Hopkins/Duke Study – Milk Allergy

• Combined SLIT/OIT for milk – ~5 months

• Pre-study milk Oral Food Challenge– Dose at reaction ~40 mg

• Initial SLIT in all groups1.

2.3.

Continued SLIT

A (low) OITB (higher) OIT

Keet, Burks, Wood et al JACI 2010

Immunotherapy Comparison

Type of Therapy OIT SLIT

Daily dose 300-4000 mg 2-7 mg

Side effects GI, systemic, fever, Oral-pharyngeal, exercise

Desensitization Large effect Smaller effect

Long term tolerance Unknown Unknown

Immunotherapy for Food Allergy - Future

• OIT/SLIT – still investigational

• Determine mechanism of action of OIT/SLIT– Basophils/mast cells, humoral, cellular

• Determine if food IT induces–

–

Desensitization without/and clinical tolerance

Is desensitization only worthwhile?

• Goal: development of active treatment for food allergy

• Studies needed to understand possible clinical benefit and mechanism• RCTs are in process• Optimizing pharmacokinetics, targeting correct populations

• Questions?

Food Allergy Immunotherapy

Contact

• Dr. Bret Haymore • 405.896.2268; 918.856.6077• drbhaymore@gmail.com• www.allergyasthmacarecenters.com• NW OKC, Midwest City, Broken Arrow

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