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Food Allergy Research Update. Kim Mudd , RN, MSN, CCRP Pediatric Allergy and Immunology Johns Hopkins University School of Medicine. Food Allergy - Prevalence. 6 – 8% of young children 3 – 4% of adolescents and adults At least 12 million Americans are affected

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Food Allergy

Research Update

Kim Mudd , RN, MSN, CCRP

Pediatric Allergy and Immunology

Johns Hopkins University School of Medicine

Food Allergy - Prevalence

  • 6 – 8% of young children

  • 3– 4% of adolescents and adults

  • At least 12 million Americans are affected

  • Prevalence similar in other developed countries although specific patterns of sensitivity vary

  • Prevalence appears to be rising (sharply)

Food Allergy Prevalence Rates

Food Young ChildrenAdults

Milk 2.5% 0.5%

Egg 1.3% 0.3%

Peanut 1 - 2% 1.0%

Tree nuts 0.4% 0.4%

Fish 0.1% 0.4%

Shellfish 0.1% 1 - 2%


Current Treatments for Food Allergy and Their Limitations

  • Strict avoidance

    • Very difficult to accomplish

    • Major impact on quality of life

    • Significant nutritional risks

  • Wait for the allergies to be outgrown

    • Peanut, tree nut, seed, fish, shellfish allergies usually lifelong

    • Milk, egg, wheat, soy, ? others now more persistent (~20% persist into adulthood and are often very severe)

  • Treat reactions when they occur

    • Reactions can be severe and even fatal

  • Potential Approaches to the Treatment of Food Allergy

    • Anti-IgE antibodies (Xolair)

    • Chinese herbal formulas

    • Immunotherapy

      • intact allergen

      • modified allergens

        • peptide vaccines

        • mutated recombinant vaccines

    • homologous proteins

    • plasmid vaccines

    • Ingestion of extensively heated milk and egg

    Potential Approaches to the Treatment of Food Allergy

    • Key questions to consider:

    • Is it allergen specific or a more general Rx?

    • Is it a treatment that may reduce risk of a severe reaction, but likely need to be used continuously, or is it a potential cure?

    • For immunotherapy, is it transient desensitization or long term tolerance?

    • How safe is it?

    • Is it feasible for general use?

    Effect of Anti-IgE on Peanut Challenge

    (Leung et al N Engl J Med. 2003)

    • Trial comparing placebo to 3 doses of TNX-901 in 84 patients

    • Rx given by SQ injection every 4 weeks x 4 doses, peanut challenges done at baseline and 2 – 4 weeks after final dose

    9 peanuts

    ½ peanut

    Dose of TNX-901

    Anti-IgE Therapy – Is this the answer?

    • Although response is variable, would at least protect most patients from reactions due to accidental exposures

    • Peanut allergy was studied but the treatment could be used for any food allergy (and provide relief for other atopic conditions)

    • But:

      • Must be given on a continuous basis

      • May not work (or be safe) if total IgE is too high

      • Unlikely to ever be approved for food allergy

      • Issues regarding safety and cost

      • May have its greatest value as an adjunct to immunotherapy

    Chinese Herbal Formulas (FAHF-1 and 2)

    • Herbal formulas based on ancient Chinese remedies for allergy

    • Appear very effective in mouse models of peanut allergy – allergic reactions on challenge, peanut IgE levels and other measures of peanut allergy were markedly reduced

    • First clinical trials for food allergy now underway with FAHF-2

      • Phase 1 safety study completed

      • Phase 1/2 study now underway to further assess safety and begin to assess efficacy

      • May also have a role as an adjunct to immunotherapy

    Immunotherapy for the Treatment of Food Allergy

    • In food allergy, the risks of traditional immunotherapy (allergy shots) appear to far outweigh the benefits

    • Alternative approaches are under investigation that may change this equation

      • Modification of the allergens

      • Different routes of delivery

        • Oral (OIT)

        • Sublingual (SLIT)

        • Epicutaneous (EPIT)

    General Approach to Immunotherapy Protocols

    Home Maintenance x 1 – 3 years

    (doses 500 mg to 4000 mg)

    Dose Escalation:

    Daily Dosing with dose increases q 1-2 weeks over 6 – 9 months

    6-12 Months

    18+ Months

    Repeat Challenges (10 grams)

    Many studies also include a final challenge off therapy to distinguish desensitization from tolerance

    Screening and


    Challenge (1g)

    Initial treatment escalation day

    (max 50 mg)

    Sublingual Immunotherapy for Hazelnut Allergy (Enrique et al, JACI 116:1073, 2005)

    • 23 patients with varying degree of hazelnut allergy divided into active and placebo groups

    • “Rush” desensitization with 22/23 reaching the planned maximum dose at 4 days



    50% could tolerate the entire 20 g challenge

    Johns Hopkins Milk OIT (Enrique et al, JACI 116:1073, 2005)Study

    (Skripak et al. J Allergy Clin Immunol2008)

    • First double-blind, placebo-controlled OIT trial, initiated in 2006

    • Children with severe, persistent milk allergy

    • Dosing

      • Milk powder or placebo powder

      • Day 1 escalation from 0.4 mg to 50 mg (1/3 tsp)

      • Then build-up from 50 mg to 500 mg (=15 ml milk)

    • Primary outcome: change in threshold dose causing reaction, as determined by oral food challenge

    • All patients completing treatment with placebo were offered open-label active therapy

    Milk Dose Threshold (Enrique et al, JACI 116:1073, 2005)

    Active (n=18)

    Placebo (n=7)

    P = 0.0003

    Milk dose (mg)

    Skripak et al. J Allergy ClinImmunol 2008

    Milk Dose Threshold (Enrique et al, JACI 116:1073, 2005)

    P = 0.003

    Milk dose (mg)

    P = 0.0003

    • FU challenge 3-17 months after open label milk protein intake:

    • 6 consumed 16,000mg with no symptoms

    • 3 consumed 16,000 mg with mild symptoms

    • 4 had mild symptoms at doses between 4.800 and 12,000 mg

    • 2 not yet re-challenged due to ongoing symptoms (but still showing increasing tolerance)

    • 3 were not eligible to continue this phase of the study

    Milk oit safety measurements
    Milk OIT Safety Measurements (Enrique et al, JACI 116:1073, 2005)

    Adverse Reactions in Open Label Follow-Up (Enrique et al, JACI 116:1073, 2005)

    • >2000 cumulative doses (median 148 per child)

    • 407 local reactions (21% of doses)

    • 74 gastrointestinal (3.8%)

    • 20 respiratory (1%)

    • Treatment: diphenhydramine for 68 (3.5%) reactions, albuterol in 12 (0.6%), epinephrine 6 (0.3%)

    • Reactions were largely unpredictable but did become less and less common over time

    • Some specific risk factors have emerged (exercise, URIs, menses)

    Cofar egg oit trial n engl j med july 2012
    CoFAR Egg OIT Trial (Enrique et al, JACI 116:1073, 2005) (N Engl J Med July 2012)

    • Design summary:

      • Randomized, placebo controlled

      • N = 55 (40 active, 15 placebo

      • 10 months escalation to 2000 mg, then OFC (“desensitization challenge”)

      • Un-blinding, 12 additional months with daily maintenance, repeat OFC

      • If OFC successful: stop dosing for 6 weeks, repeat OFC (“tolerance” challenge)

    Egg OIT Results (Enrique et al, JACI 116:1073, 2005)“Desensitization” Oral Food Challenge

    Oral Food Challenge with 5 grams of egg white performed after ~44 wks of OIT to assess desensitization

    • Results Summary: Successful challenge in 0/15 on

    • placebo compared to 21/40 (52.5%) on egg OIT (p<.001)

    Egg OIT: Oral Food Challenge (Enrique et al, JACI 116:1073, 2005) Results Summary

    • Key Results:

    • 75% were desensitized after 22 months of OIT

    • 19 out of 30 who were desensitized at 22 months lost protection after avoiding egg for 6 weeks

    • CoFAR (Enrique et al, JACI 116:1073, 2005) Peanut SLIT: Study Schematic

    • (Fleischer et al JACI 2013;131:119)


    Week 68

    OFC – 10g

    1 year on maintenance

    Week 44

    OFC - 5g

    Study Unblinding

    Week 1-36 Dose Escalation


    Maintenance Peanut SLIT

    1386 μg peanut protein/day

    Peanut SLIT

    Peanut SLIT



    Initial OFC


    Maintenance dose

    (8-28 weeks)

    1386 μg peanut protein/day

    Placebo SLIT


    Placebo SLIT

    Maintenance Peanut SLIT

    3696 μg peanut protein/day

    Week 1-36 Dose Escalation

    Week 44

    OFC – 5g

    Crossover: 16-36 Week Buildup Peanut SLIT

    followed by maintenance

    Phase III: Continued dosing x 1 – 2 years with annual OFC

    Tolerance challenges if 10 gram OFC negative

    • CoFAR (Enrique et al, JACI 116:1073, 2005) Peanut SLITStudy

    • (Fleischer et al JACI 2013;131:119)

    • Design summary:

      • Randomized, placebo controlled, N = 40

      • 2 gram peanut OFC at baseline

      • 10 months escalation to 1.3 mcg, then OFC (“desensitization challenge”)

      • Un-blinding, placebo subjects offered escalation to “high dose” SLIT (3.7 mcg)

      • 12 – 24 additional months with daily maintenance, repeat OFC annually

      • If OFC successful: stop dosing for 6 weeks, repeat OFC (“tolerance” challenge)

    Peanut (Enrique et al, JACI 116:1073, 2005) SLIT: Oral Food Challenge Baseline to Week 44




    • Active versus Placebo P=0.16

    • 70% on peanut SLIT were responders compared with 15% on placebo (P < .001)

    Responders defined as tolerating 1 gram OFC or 10-fold increase in threshold over baseline

    Oral Food Challenge Week 68 for Peanut SLIT Subjects (Enrique et al, JACI 116:1073, 2005)

    P = 0.008 baseline to week 68

    P = 0.05 week 44 to week 68

    Fleischer et al JACI 2013;131:119

    • CoFAR (Enrique et al, JACI 116:1073, 2005) Peanut SLITStudy: Safety and Study Conclusions

    • (Fleischer et al JACI 2013;131:119)

    • No significant changes were seen between the active and placebo groups

    • Significant within group changes from baseline were seen with active SLIT for OFC response as well as changes in peanut IgE and IgG4

    • Safety overall reassuring:

      • Of 10,855 peanut doses, 63.1% were symptom free; excluding oral-pharyngeal symptoms, 95.2% were symptom free

  • Conclusion: Peanut SLIT safely induced a modest level of desensitization in a majority of subjects

  • Johns hopkins milk immunotherapy study 2 a comparison of oral and sublingual immunotherapy
    Johns Hopkins Milk Immunotherapy Study #2 (Enrique et al, JACI 116:1073, 2005)A comparison of oral and sublingual immunotherapy

    SLIT (Extract)

    OIT (Powder)

    • All subjects began dosing with SLIT, then randomized to further dose escalation to:

      • SLIT: 7 mg daily (~1/20 teaspoon) given as 5 squirts x 3

      • OIT: 1000 mg (= one oz) or 2000 mg (= 2 oz)

    Study Schema Milk SLIT (Enrique et al, JACI 116:1073, 2005)vs OIT

    Food Challenge Threshold (Enrique et al, JACI 116:1073, 2005)

    At 15 mo, 10% desensitized with SLIT, 60% with OIT (p<0.001 SLIT vs. OIT)

    Milk slit vs oit challenge summary
    Milk SLIT (Enrique et al, JACI 116:1073, 2005)vs OIT: Challenge Summary

    † p=0.002 SLIT vs. OIT, ‡ p=0.09 SLIT vs. OIT by χ2

    Milk SLIT (Enrique et al, JACI 116:1073, 2005)vs OIT – Adverse Reactions

    • Overall reaction rates were similar in all groups (27 – 33% of all doses, escalation and maintenance)

    • However:

      • SLIT reactions were almost entirely local (oral)

      • While oral reactions were most common in OIT,

        • GI symptoms in 8 – 10% of doses

        • Urticaria in 4%

        • Lower respiratory in 2 – 3%

        • Multisystem reactions in 0.5 – 1%

        • Antihistamines were needed in 1% of SLIT doses compared to 16% of OIT doses

    Long-Term (Enrique et al, JACI 116:1073, 2005)Follow-up of Milk OIT

    (Keet et al, J Allergy Clin immunol 2013)

    • 32 patients followed from 2 original studies

    • 3 – 5 years after study completion:

    Symptoms at follow up n 32
    Symptoms at Follow-up (Enrique et al, JACI 116:1073, 2005)(N=32)

    *one patient had used epinephrine over 50 times in past 2 years

    Oit follow up conclusions
    OIT Follow-up: Conclusions (Enrique et al, JACI 116:1073, 2005)

    • Although we had felt that most participants in these two milk OIT trials had had very positive outcomes, 3-5 years later only 25% consume milk without symptoms

    • Over time, some subjects became far more reactive than they had been early in therapy

    • Long term success appears to be related to ongoing milk exposure (key question: why did exposure decrease from what was recommended)

    • Long-term follow-up of OIT is essential

    • OIT for food allergy is not yet ready for clinical practice

    Summary of (Enrique et al, JACI 116:1073, 2005)OIT and SLIT Study Results

    • SLIT appears to be less effective than OIT, although this could change with better delivery methods

    • In small studies of children with significant milk, peanut, and egg allergy, OIT appears capable of inducing significant changes in threshold for clinical reactivity

    • “Tolerance” is only accomplished in a minority of patients

    • Rates of adverse reactions are significant but likely acceptable, esp if most develop long term tolerance

    • Further study is clearly warranted to decrease adverse reactions and improve efficacy, including induction of long term tolerance

    • Should be limited to controlled, IRB / FDA approved research protocols at this time

    Ingestion of “Heat-Denatured” Milk or Egg (Enrique et al, JACI 116:1073, 2005)

    • Milk (and egg) allergic children can be divided into several groups:

      • Group 1: Severe, more persistent, react to all forms of milk or egg

      • Group 2: Less severe, easier to outgrow, do not react to extensively heated (baked) products, espat lower doses

      • Children in group one may eventually move into group two

  • In those children in group 2, it may be safe to introduce milk or egg in a baked form without doing harm, and possibly helping to increase tolerance

  • Breaks the old dogma of strict avoidance until outgrown

  • Present and Future Initiatives (Enrique et al, JACI 116:1073, 2005)

    • Examples of current studies:

      • Comparative study of SLIT vs OIT for peanut allergy

      • Combination of Xolair and milk OIT

  • Egg oral immunotherapy vs baked egg

    • Epicutaneous IT for peanut allergy (peanut patch)

    • Wheat OIT

    • Peanut OIT in 1 – 3 year olds

    • Dissolving film for peanut SLIT

    • Many other studies are ongoing around the world, including new approaches being studied in animal models

  • Progress will be slow – partly due to funding but primarily to maximize safety – but reasonably effective Rx for severe, persistent food allergy will be developed for general use in the next 10 years

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