Peanut Allergy: Natural History and Prospects for Treatment

1
Peanut Allergy Natural History and Prospects
for Treatment
Robert A. Wood, MD Professor of
Pediatrics Director, Pediatric Allergy and
Immunology Johns Hopkins University School of
Medicine
2
Peanut Allergy - Overview

• Common in both children and adults
• 3rd most common food allergy in children
• Most common food allergy in adolescents and
  adults
• Average age of onset 18 months
• Reactions are often very severe
• Prevalence appears to have risen sharply in
  recent years

3
Peanut Allergy Prevalence Studies

• Isle of Wight prospective study of 1218
  infants peanut allergy developed in 1.1
• 1997 - US telephone survey of 4374 households
  peanut allergy reported in 0.4 of
  children and 0.7 of adults
• 2002 same study repeated, now with PA reported
  in 0.8 of children
• Similar increases have occurred for other foods
  and other allergic diseases

4
Food Allergy Prevalence Rates
Food Young Children Adults Milk 2.5
0.3 Egg 1.3 0.2 Peanut 0.8
0.6 Tree nuts 0.4 0.4 Fish 0.1
0.4 Shellfish 0.1 2.0 Overall 6.0
3.7
5
Why Is the Prevalence Rising?

• Theories include
• Hygiene hypothesis
• Infection
• Changes in diet
• Environmental factors
• Immunizations
• Vitamin deficiencies

6
Peanut Allergy - Sensitization

• Reactions reported to occur on 1st known exposure
  in 80 of cases
• Possible explanations
• Failure to recall prior exposures or unsuspected
  exposure
• Exposure through topical preparations, incidental
  skin contact, or inhalation
• In utero exposure
• Exposure via breast milk

7
Peanut Allergy - Sensitization

• Does in utero exposure / sensitization occur?
• 25 children with peanut allergy compared to
  18 children with other food allergies
• Peanut allergy was more common if mothers had
  ingested peanut more than once a week in
  pregnancy ? odds ratio 3.97
• However, peanuts were also introduced at an
  earlier age in those with peanut allergy (P0.03)

8
Peanut Allergy - Sensitization

• Exposure via breast milk
• Peanut (and other food) allergens pass readily
  into the breast milk
• The prevalence of peanut allergy is higher in
  breast fed infants
• In one study it was found that consumption of
  peanuts while breast feeding was more common
  among mothers of peanut allergic children lt5 yrs
  versus those gt5 yrs (Plt0.001) and that breast
  feeding was associated with an earlier onset of PA

9
Peanut Allergy Genetic Influences

• Peanut allergy is clearly more common in atopic
  families
• Hourihane found that 8 of siblings of PA
  children also had peanut allergy
• Sicherer found in a study of PA in twins that
  10/14 monozygotic twins were concordant for PA,
  compared to 4/44 dizygotic twins
• Overall heritability of PA estimated to be 80

10
Peanut Allergy Clinical Characteristics

• Accidental ingestions are common about 50 will
  experience an accidental reaction in any 5 year
  period
• Reactions range from mild to fatal and overall
  tend to be more severe than for other foods
• Reactions often become more severe over time, but
  severity will vary depending on level of
  sensitivity, dose, and route of exposure

11
Peanut Allergy Clinical Characteristics
(VanderLeek et al J Peds 2001)

• 85 children with PN allergy, 55 followed for
  gt5 years
• 58 had at least one accidental rxn in 5 yr
  FU, 75 in 10 yr FU
• Rxns tended to become more severe with time and
  52 included potentially life-threatening Sx
• Severe reactions were associated with high
  PN-IgE levels

12
Fatal Food-induced Anaphylaxis

• Fatal reactions are on the rise
• 150 200 deaths per year
• Usually caused by a known allergy
• Three well defined risk factors
• Peanut and tree nut allergy
• Asthma
• Failure to treat promptly w/epinephrine
• Many cases exhibit biphasic reaction

13
Peanut Allergy Natural History

• Until recently was thought to virtually always be
  lifelong
• Bock Atkins 1989
• Followed 32 children 1 to 14 yrs of age with
  peanut allergy for 2 to 14 yrs
• 24 had reactions due to accidental exposures
• None appeared to lose their allergy

14
Studies on the Natural History of Peanut Allergy
(Skolnick et al (JACI 2001107367)

• 223 patients between the ages of 4 and 18 yrs
  with a diagnosis of peanut allergy
• Challenges offered to those with a PN-IgE lt20
  kU/L (by CAP-RAST) and no reaction in past year
• Also assessed skin tests and other clinical
  parameters (other food allergies, other allergic
  diseases, severity of prior reactions) as
  predictors of natural history

15
Patient Characteristics
16
Summary of Results

• 21.5 of children above the age of 4 with PN
  
  
  
  
  allergy were shown to have outgrown their
  allergy
• PN-IgE levels at dx and at evaluation were
  signifi-
  
  
  
  cantly lower in those outgrowing
  their PN allergy
• Negative challenges in
• 61 with a PN-IgE lt5 KU/L
• 67 with a PN-IgE lt2
• 73 with a PN-IgE lt0.35
  
  
  
  
• Only 2 patients with a PN RAST gt10 at diagnosis
  were shown to have outgrown their PN allergy

17
Fleischer et al (JACI 2003112183)
84 additional patients, all with PN-IgE levels
5 at challenge

• Children with PN-IgE levels 2 were
  significantly more likely to pass than those with
  levels between 2 and 5 (plt0.003)

18
Peanut Allergy Risk of Recurrence Fleischer et
al (JACI 20041141195)

• One patient from our previous studies with
  definite recurrence as well as several reported
  elsewhere
• Also found in previous study that most patients
  were still avoiding peanut, though not as
  strictly
• 68 of 96 patients (71) from prior studies
  recruited
• Questionnaire detailing characteristics of peanut
  ingestion and any reactions to peanut since
  passing challenge
• Patients also offered repeat skin, CAP-RAST
  testing, and double-blind, placebo-controlled,
  food challenge (DBPCFC)

19
Peanut Allergy Risk of Recurrence Fleischer et
al (JACI 20041141195)

• 3 definite recurrences, with an overall
  recurrence rate of 8
• The 3 patients who had recurrences consumed
  peanut infrequently, compared to no recurrences
  in the patients who ate peanut regularly
  (p0.025)
• 3 other patients passed challenges in spite of
  significant rise in PN IgE (7.6, 17.1, and 54
  kU/L)
• Now recommend regular peanut consumption once
  tolerant

20
The Natural History of Tree Nut
Allergy (Fleischer et al, JACI 2005)

• 275 children with tree nut allergy were studied
• 9 of the 275 subjects (95 CI 4.7 13.3)
  outgrew their allergy
• 58 with TN-specific IgE lt5 kU/L and 63 lt2 kU/L
  passed their challenges
• No one with allergy to more than 2 tree nuts
  outgrew their allergy
• No other factors predicted who would outgrow
  their allergy (such as reaction severity)

21
Natural History of Peanut Allergy - Current
Approach

• All children with peanut (and tree nut) allergy
  
  
  
  
  should be re-evaluated every 1 - 2 years,
  at least up to the age of 6
• The CAP-RAST is the preferred method of
  
  
  
  
  evaluation
• Selected patients should undergo challenge
• Age gt 4 years
• No reaction in past 1-2 years
• CAP-RAST lt2 kU/L

22
Food Allergy Possible Prevention Strategies

• Avoid all peanuts and tree nuts in the last
  trimester of pregnancy and while breast feeding
• Do not introduce peanuts, tree nuts, fish, and
  shellfish until age 3 years
• In highly atopic families
• Consider avoidance of milk and egg while breast
  feeding
• Supplement with hypoallergenic formula
• Delay intro of allergenic foods until at least
  age one

23
Food Allergy - Treatment

• Strict avoidance
• Treatment of reactions
• Immunotherapy / future therapies

24
Peanut Allergy - Avoidance

• Read all labels, avoid may contain products
• Avoid other high risk foods
• Baked goods
• Ethnic (especially Asian) foods
• Candies
• Ice creams
• ? Peanut free homes, classrooms, schools
• Airlines, other sources of airborne exposure

25
Food Allergy Treatment of Reactions

• Complete avoidance is impossible
• Must always be prepared to treat a reaction
• Have an emergency action plan
• Keep self-injectable epinephrine on hand at all
  times
• Train caregivers and teachers on EpiPen? or
  Twinject use
• Wear MedicAlert? bracelet

26
Approaches to the Treatment of Food Allergy

• Anti-IgE antibodies (Xolair)
• Immunotherapy
• intact allergen
• modified allergen (vaccine)
• routes of delivery
• oral, subcutaneous, rectal
• Chinese herbal remedy
• Others

27
Approaches to the Treatment of Food Allergy

• Anti-IgE Antibody Therapy
• These antibodies block the interaction of
  
  
  
  
  allergen with IgE and thereby reduce or
  prevent allergic reactions
• Given by injection every 2 4 weeks
  
  
  
  
• This has proven moderately effective in
  
  
  
  
  allergic asthma and allergic rhinitis
• One study on the treatment of food allergy has
  been completed

28
Effect of Anti-IgE Therapy in Patients with
Peanut Allergy (Leung et al, NEJM 2003348986)

• Methods
• Double-blind trial comparing placebo to 3 doses
  of TNX-901 (150, 300, and 450 mg)
• Rx given by SQ injection every 4 weeks x 4 doses
• Peanut challenges done at baseline and 2 4
  weeks after final dose
• 84 patients were studied

29
Effect of Anti-IgE on Peanut Challenge
Dose of TNX-901
30
Anti-IgE Therapy How encouraged should we be?

• TNX-901 clearly increased ability to tolerate
  peanut in a majority of patients (although some
  patients did not get any protection)
• Dose related effect
• At the highest dose, would protect most patients
  from reactions due to accidental exposures
• Peanut allergy was studied but the treatment
  could be used for any food allergy
• Must be given on a continuous basis (this is a
  medicine, not a vaccine)

31
Anti-IgE Therapy Unanswered Questions

• Will it work in highly allergic patients?
• Will not work if total IgE level too high (gt1000)
• Legal issues (TNX-901 will not be studied
  further)
• Will Xolair be as effective as TNX-901
• Significant issues in getting Xolair approved
• Safety concerns
• Cost concerns
• If approved, who should be treated?

32
Approaches to the Treatment of Food Allergy
Chinese Herbal Formula (FAHF-1)

• Peanut allergic mice were treated with FAHF-1 for
  7 weeks and then re-challenged
• Peanut IgE levels and other measures of peanut
  allergy were markedly reduced
• Allergic reactions on challenge were completed
  eliminated
• No side effects were seen
• Encouraging, but unclear how far this will go

33
Approaches to the Treatment of Food Allergy

• Immunotherapy
• Induces tolerance to an allergen by giving
  
  
  
  
  gradually increasing doses of the allergen
• In food allergy, the risks of traditional
  immunotherapy have far outweighed
  
  
  
  the
  benefits
• New approaches may allow this equation
  
  
  
  
  to change by altering the allergen to
  
  
  
  
  produce the positive effect with
  little or
  
  
  
  no negative effect

34
Approaches to the Treatment of Food Allergy
The Peanut Allergen Ara h 2
LTILVALALF LLAAHASARQ QWELOGDRRC QSQLERQNLR
PCEQHLMQKI QRDEDSYERD
IgE Binding Site T Cell
Binding Site
Stimulates T cells but does not bind to IgE
will not cause an allergic reaction
With this information, immunotherapy could be
developed that only contains the relevant T cell
binding segments
35
Development of a Peanut Vaccine

• Animal studies with dramatic results
• The current vaccine contains epitopes from 3
  major peanut allergens (named EMP-123 -
  Encapsulated, Recombinant Modified Peanut
  Proteins Ara h 1, Ara h 2, and Ara h 3)
• Proposed to give rectally (suppository) by
  increasing doses over 8 weeks, then 3 maintenance
  doses given every 2 weeks
• First human trials expected to start in the next
  18 months
• The process will be slow but this may be the best
  hope for an effective long term treatment

36
Approaches to the Treatment of Food Allergy

• Oral or Sublingual Immunotherapy
• Induces tolerance to an allergen by giving
  
  
  
  
  gradually increasing doses, in this case
  either under the tongue or swallowed
• Several preliminary studies with very encouraging
  results strong evidence of at least short term
  desensitization
• Questions as to risks and potential for long term
  tolerance

37
Sublingual Immunotherapy for Hazelnut Allergy
(Enrique et al, JACI 1161073, 2005)

• 23 patients with varying degree of hazelnut
  allergy divided into 2 treatment groups
• Twenty-two patients reached the planned maximum
  dose at 4 days
• Systemic reactions were observed in only 0.2 of
  the total doses administered
• Mean hazelnut quantity provoking symptoms
  increased from 2.29 g to 11.56 g (P .02 active
  group) versus 3.49 g to 4.14 g (placebo NS)
• 50 of patients who underwent active treatment
  reached the highest dose (20 g), but only 9 in
  the placebo

38
Oral challenge tests mean food amounts tolerated
in patients with hazelnut SLIT and placebo SLIT
before and after immunotherapy.
39
Present and Future Initiatives

• The Food Allergy Research Consortium - NIH
  sponsored consortium dedicated to the study of
  food allergy
• 2 current studies
• Observational study of infants with food allergy
• Oral immunotherapy study using egg protein
• Planning
• Oral peanut immunotherapy study
• Peanut vaccine study
• Starting trial of oral milk immunotherapy next
  month
• Two new Xolair studies are being planned to start
  in 2007
• Human studies of the Chinese Herbal Formula will
  hopefully start in the next 2 years

40
Peanut Allergy - Summary

• Peanut allergy is common, affecting about 0.6 of
  the US population
• Accidental reactions are common and often severe
• Some peanut allergy might be prevented by
  delaying exposure in early life
• Most but not all peanut allergy is lifelong
• Truly effective treatment will be possible in
  the next 10-20 years