Breakthroughs in Food Allergy: Keeping Nutritious Foods at the Table

Transcription

1 Breakthroughs in Food Allergy: Keeping Nutritious Foods at the Table Pamela H. Steele, MSN, CPNP, AE-C Pediatric Allergy and Immunology Duke University Medical Center Durham, NC

2 Pamela H. Steele Financial: None Research: None Legal Consult/Expert Witness: None Organizational: None Gifts: None Other: None

3 What is Oral Tolerance Specific suppression of cellular and humoral immune responses to an antigen by means of prior administration through the oral route

4 What is Food Allergy Failure to develop oral tolerance Disruption in previously established oral tolerance Requires an initial encounter with the antigen

5 Normal Immune Response Food presented to the GI tract Largest immunologic organ Populated with lymphocytes Daily exposures to bacteria and ingested protein Dietary protein antigen interacts with Antigen Presenting Cells (APCs) APCs activate regulatory T cells which results in suppressing the immune response

6 Abnormal Immune Response Food specific antibodies are formed Antibodies bind to receptors on the mast cell and basophils Exposure to sensitized food occurs Food antigen binds to the food specific antibody resulting in a release of mediators Histamine Prostaglandins Leukotrienes Cytokines Allergic symptoms occur

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8 Risk Factors for Food Allergy Genetic predisposition First degree relative Early life factors Maternal and infant diet Presence of co-morbid eczema Immunological stimuli Hygiene Hypothesis

9 History of Food Allergy Treatment Reported as early as 1930 as a rush inoculation 1992 treatment of peanut allergy reported with rush immunotherapy 1997 peanut allergy treatment with injections of aqueous peanut extracts

10 Rationale for Treatment Tremendous burden and stress Prevalence and incidence rising New data reveal that egg and milk appear to be outgrown later in life Only 10 to 20% outgrow peanut and tree nut allergy Improve quality of life

11 Why is Research Needed? Increasing numbers of people affected by food allergy Adults: 2 to 3% Infants/ children 6 to 8% (250,000 births) Major allergens common in the western diet Food induced allergic reactions #1 reason for ER visits due to anaphylaxis Only treatment is avoidance Attempts at prevention unsuccessful

12 Basis of Research Alter the immune system s response to food allergens Include different focuses of immunotherapy Cytokine-modulated Allergen-peptide Engineered (mutated) allergen protein

13 Goals of Research Increase the threshold of the food protein to which the person is allergic Reduce the severity of a reaction Induce long lasting tolerance

14 Food in Schools and Child Care Settings Sampson s landmark study in 1992 in JACI Significant delays in epinephrine administration (average time of 75 minutes) Inadequate management plans Deficiencies in recognizing reactions Should foods be banned? Inhalation exposures Only case reports (self reports or questionnaires) Aroma of peanut (no protein) Craft projects Cleaning of hands and table surfaces Hand washing with soap and water or commercial wipes Alcohol based hand sanitizers not effective Risk of exposure Younger the child greater the risk Perry et al JACI 2004

15 Sublingual Route (SLIT) Administration of a liquid antigen extract under the tongue for a specific duration Two modalities of administration Hold antigen and swallow (SLIT) Dose held for various amounts of time (30sec 4 min) before swallowed Hold antigen and spit (Sublingual Spit)

16 Mechanism of SLIT Contact with oral mucosa is critical Sublingual discharge vs sublingual swallow Local Langerhan-like dendritic cells important Allergen-specific IgE results variable, may be decreased Allergen-specific IgG/IgG 4 results variable, may be increased somewhat Allergen-specific IgA unknown Akdis Allergy 2006

17 SLIT Side effects less than what has been seen with OIT Majority of side effects involve oral pruritus and tingling These symptoms usually resolve with eating an ice popsicle, ice chips, or drinking cold liquids Systemic reactions can occur, but less likely

18 Food Allergy Treatment: SLIT Mempel, et al. reported in JACI 2003 treatment of severe anaphylaxis to kiwi fruit with SLIT Kerzl et al reported lasting protective effect of SLIT after discontinuation in JACI 2007

19 Sublingual Immunotherapy (SLIT) SLIT hazelnut allergy in adults DBPC, multi-center study, adults w/ hazelnut allergy (n=22) Sublingual-discharge technique 4 day rush build-up, 8-12 week daily SLIT (66 mg) Primarily OAS patients benefited Enrique et al J Allergy Clin Immunol : SLIT peanut-allergic children and adults (1) Initial pilot study (Duke) - Adolescents and adults (2) 2 nd -blinded study (Duke) - Children (3) 3 rd study (CoFAR) - Adolescents and adults 3 year study Laubach, Burks, et al. J Allergy Clin Immunol 2008;121:S96 Bird et al. J Allergy Clin Immunol 2009

20 Desensitization Aims of OIT Increases the threshold for an allergic reaction to the particular food Starts with multiple doses on the first day followed by single daily doses at home Build-up of dosing over time Tolerance Change the food specific immune response of the subject

21 OIT Studies for PN - Arkansas and Duke OIT Study Design 300 mg Dose Dose Escalation Maintenance 300 mg 4 mo 28/29 ingested 7.8 gm On OIT 300 mg dose 1 had allergic symptoms (one hive, sneeze) - challenge was stopped at 2100 mg due to parental concern 7.8 gram Food Challenge Initial escalation day Desensitization 300 mg = 1 peanut

22 Peanut OIT Subjects Enrollment criteria - Any peanut-allergic subject - including history of anaphylaxis (unless accompanied by significant hypotension) Age at enrollment: Mean 57 months (range ) Age at first reaction: Mean 15 months (range 8-48) Peanut CAP FEIA: Mean 148 ku/l 29 of 33 subjects completed - Duke and Arkansas sites 4 - allergic side-effects more than parents/investigators comfortable Jones, Burks et al. J Allergy Clin Immunol August 2009

23 Side effects of OIT Change in usual state of health Subject s demeanor Activity level Skin Rash Angioedema Urticaria Pruritus Gastrointestinal Nausea Vomiting Abdominal pain Diarrhea Oral Mouth tingling/itching Hoarseness Upper respiratory Sneezing/Itching Rhinorrhea Nasal congestion Cough Lower Respiratory Wheeze Shortness of breath Respiratory distress Cardiovascular compromise

24 Safety of Peanut OIT Dosing Symptoms Initial Escalation Day Buildup Phase Home Dosing Phase Any 93% (77%, 99%) Upper 79% Respiratory (59%, 92%) Skin 61% (41%, 79%) Abdominal 68% (48%, 84%) Chest 18% (6%, 37%) 46% (37%, 56%) 29% (20%, 41%) 24% (17%, 32%) 5.5% (3.2%, 9.2%) 1.7% (0.6%, 5.1%) 3.5% (2.3%, 5.1%) 1.2% (0.6%, 2.5%) 1.1% (0.7%, 1.8%) 0.9% (0.6%, 1.4%) 0.3% (0.1%, 0.4%) Risk of Symptom Occurrence with 95% Confidence Intervals Hofmann et al JACI 2009

25 Peanut OIT Dosing Adverse Reactions Patterns of reactions have surfaced Dosing with fever/illness Suboptimally-controlled asthma Exertional (exercise) symptoms Timing of dose Menses Changed OIT protocol after first open study Recommendations may improve safety of investigational protocols Varshney P, Jones SM, Burks AW et al, JACI 2009

26 OIT Study Design 4000 mg Dose Maintenance 4000 mg Stop OIT if criteria met Dose Escalation 1 mo 300 mg = 1 peanut 10 gram Food Challenge 10 gram Food Challenge Tolerance Initial escalation day Desensitization 10 gram Food Challenge Jones AAAAI 2010

27 Milk OIT - Johns Hopkins and Duke 19 milk-allergic subjects - 6 to 17 years 12 active, 7 placebo Build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg) Daily doses with 8 weekly in-office dose increases to a maximum of 500 mg Daily maintenance doses for 3 to 4 months Median milk threshold dose 40 mg at the baseline challenge After OIT DBPCFC -Active mg vs. Placebo - 40 mg (P =.0003) End-point titration SPT Active vs. Placebo (P=.03) Skripak et al J Allergy Clin Immunol ;6: Narisety SD J Allergy Clin Immunol Sep;124(3): Epub 2009 Aug 8

28 Heated Protein Studies Lemon-Mulé et al reported in JACI 2008 the results of a study evaluating tolerance to heated egg in egg allergic subjects Nowak-Wegrzyn et al reported the results of JACI 2008 results of a heated milk study in milk allergic subjects

29 Clinical Considerations for Heated Protein Challenges IgE levels Undetectable serum level of ovomucoid specific IgE for egg Milk specific IgE < 5 kua/l for milk Long term effect of the introduction of heated food in diet unknown Amount of protein to be offered during the challenge Educating parents before offering the choice of a challenge

30 Consortium of Food Allergy Research (COFAR) NIH multi-site funded study Participating Centers Duke University Medical Center University of Arkansas Medical Center Mt. Sinai Medical Center Johns Hopkins Medical Center National Jewish Medical Center

31 Engineered Recombinant Proteins Identified the peanut allergens Ara h 1-3 (Arachis hypogaea) and with the gene produced peanut proteins in the laboratory Identified IgE-binding epitopes on Ara h 1 3 Substituted single amino acid within epitope e.g. Ara h 2 a.a DRRCQSQLER eliminated or markedly reduced IgE binding T cell response unchanged Utilized the engineered peanut protein in a mouse model of peanut allergy new proteins prevented anaphylaxis in the peanut-allergic mice Initial human safety studies through CoFAR started in 2009 Sampson and Burks et al. Burks J Allergy Clin Immunol ;1344

32 Currently Active Protocols Recombinant protein: EMP-123 (COFAR) Heated proteins: milk (Mt. Sinai) Adjunctive treatments Omalizumab + milk OIT (Mt. Sinai) Food allergy herbal formula-2 (Mt. Sinai)

33 Currently Active Protocols Egg OIT (COFAR) Heated Egg / OIT to Egg Peanut OIT (Duke/Arkansas, Stanford) Peanut OIT with probiotics (Australia) Peanut SLIT (Duke/COFAR) Milk SLIT vs. OIT (Johns Hopkins/Duke) SLIT with various food allergens (Missouri) EoE (COFAR)

34 Questions to be Answered How do we determine the starting dose? How often do we increase the dose? What is the amount required for maintenance? When do we challenge?

35 Determining the Starting Dose Challenges for determining threshold dose to start Minimum dose to maximum dose Acceptable amount of subject symptoms Safety of home dosing

36 Maintenance Determination Is a maintenance amount necessary or do we keep pushing the dose Food serving size Time on treatment Minimum amount required to be successful

37 Summary Food allergy is believed to be the result of a breakdown in normal oral tolerance induction Therapies may offer protection from potentially life threatening reactions Paramount goal is to induce life long tolerance

38 References Akdis CA, Barlan IB, Bahceciler N, Adkis. Immunological mechanisms of sublingual therapy. Allergy 2006:61 (Suppl.81): Buchanan AD, Green TD, Jones SM, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol 2007, 119: Burks AW, Laubach S, Jones SM. Oral tolerance, food allergy, and immunotherapy: implications for future treatment. J Allergy Clin Immunol 2008, 121: Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol 2003;111: Cochran Library, Issue 2, Oxford: Update Software Eigenmann PA. Mechanisms of food allergy. Pediatric Allergy and Immunology 2009; 20: Enrique E, Pineda F, Makek T. et al. Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 2005;116: Frew AJ, White PJ. Sublingual immunotherapy. J Allergy Clin Immunolo 1999;104: Hoffman AM, Scurlock AM, Jones SM, Palmer KP, Lokhmygina Y, Steele PH, Kamilaris J, Burks AW. Safety of a peanut oral immunotherapy protocol in children with peanut allergy. J Allergy Clin Immunol 2009;124:

39 References Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, Francis JM, Durham S, Vickery BP, Zong X, Burks AW. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunolo2009;124: Kerzl R,et al Life-threatening anaphylaxis to kiwi fruit: Protective sublingual allergen immunotherapy effect persists even after discontinuation. J Allergy Clin Immunol 2007, 119: Lemon-Mule H, Sampson HA, Sicherer SH, et al. Immunologic changes in children with egg allergy ingesting extensively heated egg. J Allergy Clin Immunol 2008, 122: e1. Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-ige therapy in patients with peanut allergy. N Engl J Med 2003, 348: Longo G, Barbi E, Berti I, et al. Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy Clin Immunol 2008, 121: Meglio P, Bartone E, Plantamura M et al. A protocol for oral desensitization in children with IgE-mediated cow s milk allergy. Allergy 2004;59: Memphel M, Rakoski J, Ring J, Ollert M. Severe anaphylaxis to kiwi fruit: Immunologic changes related to successful sublingual allergen immunotherapy. J Allergy Clin Immunol 2003;111:

40 References Niggemann B, Staden U, Rolinck-Werninghaus et al. Specific oral tolerance induction in food allergy. Allergy 2006:61: Nowak-Wegrzyn A, Bloom KA, Sicherer SH, et al. Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol 2008, 122:342-7, 347.e1-2. Pausquet J. Suglingual Immunotherapy: Validated! Allergy 2006:61:(Supple. 81):5-6. Passalacqua G, Buerra L, Compalati E et al. New insights in sublingual immunotherapy.curr Allergy Asthma Rep Sep;6(5): Paatriarca G, Nucera E, Roncallo C et al. Oral desensitizing treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther 2003;17: Panzner P, Petras M, Sykora T, et al. Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralingually. Respir Med Perry, TT, Conover-Walker,MK, Pomes, A, Chapman, MD, Wood, RA. Distribution of peanut allergen in the environment. JACI 2004; 113: Qu C, Srivastava K, Ko J, et al. Induction of tolerance after establishment of peanut allergy by the food allergy herbal formula-2 is associated with up-regulation of interferon-gamma. Clin Exp Allergy 2007, 37:

41 References Sampson HA. Update on Food Allergy. J Allergy Clin Immunolo 2005;113(5): Scurlock AM, Steele PH, Andrzejewski SS et al. Safety of oral peanut immunotherapy for peanut allergic patients. J Allergy Clin Immunol 2005;115:S246. Skripak JM, Nash SD, Rowley H, et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF- 2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol 2005, 115: Staden U, Blumchen K, Blankenstein N, et al. Rush oral immunotherapy in children with persistent cow's milk allergy. J Allergy Clin Immunol Staden U, Rolinck-Werninghaus C, Brewe F, et al. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 2007, 62: Vickery BP, Burks AW. Immunotherapy in the treatment of food allergy: focus on oral tolerance. Current Opinion in Allergy and Clinical Immunology 2009, 9: Young, MC, Munoz-Furlong, A, Sicherer, SH. Management of food allergies in schools: A perspective for allergists. J Allergy Clin Immunolo 2009; 124(2):