Kari C. Nadeau, MD, PhD Division of Allergy , Immunology, and Rheumatology at Stanford Describe the pathophysiology, initial evaluation & management of patients with food allergy including gastrointestinal food allergy, oral allergy syndrome and type I food allergy Identify recent advances in the field of food allergy and have some familiarity with published guidelines for managing food allergy Outline current and emerging treatment modalities for food allergic patients
Nothing to disclose ID: 9.5 y.o. male with a history of severe food allergies, eczema, and asthma CC: Presents to PICU with hypoxic brain injury due to anaphylaxis from cow’s milk ingestion Transferred to PICU from outside hospital after multiple failed resuscitations over a 3 hr period On the evening of 8-11-04, patient accidentally drank from his sister’s cup of cow’s milk on the way to bed. He immediately developed emesis and became SOB; parents gave Epipen jr. to his thigh and called 911 Paramedics arrived in 10-15 minutes On the scene, intubation was attempted but difficult Duration of code=1 hr. CT scan showed hypoxic injury and right uncal herniation. In 2001, he presented to LPCH AAI clinic and had severe eczema and asthma. RAST tests were performed at 2001 and showed IgE > 2000, Milk> 100, Peanut>100, Egg 40.3, Soy 17.9, Wheat 20.2, Corn 26.3, Oat 12.3. No known allergies to beef. He had had one prior visit to the ER for milk ingestion in 2001. He presented with hyperventilation and emesis. He was given benadryl and his symptoms improved. He was hospitalized three times in the first year of life for asthma; no intubations but did need steroids Patient and family were prescribed an Epipen jr. and taught about anaphylaxis precautions Patient then began to receive care at private AI facility and was recommended 9 months prior to event to repeat RAST testing. This was not done. Over the past couple of months prior to event, parents decided to allow him to eat wheat, corn, oat, and egg products since he did not seem to have any symptoms from these foods.
Background Definition Clinical signs and symptoms Natural History . Cow’s milk, hen’s egg, soy, peanut, tree nuts Diagnostic work-up Treatment Research studies and FAQs
Prevalence ~4% - Peanuts – 3 million allergic in U.S. (~1.1%) Branum 2009 Pediatrics 124:1549-55
Most common cause of visits for pediatric anaphylaxis treated in U.S. Emergency Rooms
> 15% of patients/year have accidental reactions Yu 2006 J Allergy Clinical Immunology 118: 466-472
100-150 deaths/year reported from food allergies - Bock SA J Allergy Clinical Immunology 2001: 107 (1): 191-193 Food culprits (n=79) . Peanut 56% . Tree nut 24% . Fish/shellfish 8% . Milk 9% . Wheat 1% . Unknown 3% Mixed nuts, baked goods, cookies, candies, Ethnic food, buffets, sauces, cross-contamination Bock S.A. AAAAI meeting 2009 . Adolescents . Nut Allergy . Known food allergy . History of Anaphylaxis . Asthma, especially those with poor control . Lack of skin symptoms . Denial of symptoms . Concomitant intake of alcohol (which may increase absorption of food) . Belief that antihistamines alone were sufficient to treat symptoms . Delay or lack of administration of epinephrine . However even timely injections of epinephrine do not necessarily prevent death (4 of 32 cases)
Bock SA J Allergy Clinical Immunology 2001: 107 (1): 191-193
Can occur in 30-60 minutes Due to upper or lower respiratory compromise or cardiovascular collapse . Pumphrey et al. Clin Exp Allergy 30 (2000): 1144–1150.
Adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.
National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010
National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010 Signs and symptoms Percentage of cases Cutaneous >90 Urticaria and angioedema 85–90 Flush 45–55 Pruritus without rash 2–5 Respiratory 40–60 Dyspnea, wheeze 45–50 Upper airway angioedema 50–60 Rhinitis 15–20 Dizziness, syncope, 30–35 hypotension Abdominal Nausea, vomiting, 25–30 diarrhea, cramping pain Miscellaneous Headache 5–8 Substernal pain 4–6 Seizure 1–2 Over 170 foods have been reported to cause IgE-mediated reactions However over 90% of food allergies are caused by the following foods . Milk . Hen’s egg . Soy . Wheat . Peanut . Tree Nuts . Shellfish . Fish National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010
Children with food allergy*: . 35-71% atopic dermatitis ▪ Possible that peanut sensitization is associated with atopic dermatitis, use of peanut oil containing skin preparations, and household consumption of peanut** . 33-40% allergic rhinitis . 34-39% asthma
* Sicherer et al. J of Allergy and Clin Immunology 2001: 108: 128-32 ** Fox et al. J of Allergy and Clin Immunology 2009: 123 (2): 417-23.
Oral pruritus, rapid onset, IgE-mediated, rarely progressive Usually fresh fruits and vegetables Heat labile: cooked forms, no reaction Cause: cross reactive proteins pollen/food Birch Apple, apricot, carrot, cherry, kiwi, plum Ragweed Banana, cucumber, melon, watermelon Grass Cherry, peach, potato, tomato Pollen Foods Enterocolitis Enteropathy Proctitis
Age Onset: Infant Infant/Toddler Newborn
Duration: 12-24 mo 12-24 mo 9 mo-12 mo
Characteristics: Failure to thrive Malabsorption Bloody stools Shock Villous atrophy Lethargy Eosinophilic Diarrhea Self limited Vomiting
Non-IgE-mediated, typically milk and soy induced Spectrum may include colic, constipation and occult GI blood loss Celiac Disease (Gluten-sensitive enteropathy) . Anti-gliadin IgG, anti-endomysial IgG, IgA . Villus atrophy, malabsorption, pain, associated CA Eosinophilic esophagitis, gastritis, gastroenteritis . Eosinophilic infiltration . Poor growth, pain, vomit, diarrhea, reflux . Multiple food allergy, IgE and non-IgE-mediated . May affect varying regions of gut Gastrointestinal Anaphylaxis . Acute vomit/diarrhea, IgE-mediated
Migraines Behavioral / Developmental disorders Arthritis Seizures Inflammatory bowel disease What is not a food allergy? Condition Symptoms Mechanism Bloating, abdominal pain, diarrhea Lactose intolerance Lactase deficiency (dose-dependent) Bloating, abdominal pain, diarrhea Fructose intolerance Fructase deficiency (dose-dependent) Pancreatic Malabsorption Deficiency of pancreatic enzymes insufficiency Gallbladder/liver Malabsorption Deficiency of liver enzymes disease Pain, fever, nausea, emesis, Food poisoning Bacterial toxins in food diarrhea Scombroid fish Flushing, angioedema, hives, In spoiled fish histidine is metabolized to poisoning abdominal pain histamine Pharmacologic effects of caffeine in susceptible Caffeine Tremors, cramps, diarrhea individuals Pharmacologic effects of tyramine in susceptible Tyramine Migraine individuals Auriculotemporal Facial flush in trigeminal nerve Neurogenic reflex, frequently associated with syndrome (Frey distribution associated with birth trauma to trigeminal nerve (forceps syndrome) spicy foods delivery) Profuse watery rhinorrhea Gustatory rhinitis Neurogenic reflex associated with spicy foods Subjective reactions, fainting upon Panic disorder Psychologic smelling or seeing the food Most children will outgrow cow’s milk, egg, and wheat allergy Far fewer will outgrow peanut and tree nut allergy A high initial specific IgE against the food is associated with a lower rate of resolution of clinical allergy over time Atopic dermatitis resolution is a useful marker for onset of tolerance to food allergens Skin tests to a food can remain positive long after tolerance to a food has developed. Nevertheless, reduction in the size of the skin test wheal may be a marker for the onset of tolerance to the food allergen. National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010
First foreign protein introduced into infant’s diet Most common food allergy in young children . 2.5% of children in first two years of life . 1.1% is IgE-mediated
Minimal threshold dose to cause allergic reaction as low as 0.02 mL of milk (e.g. drops)
Cross-reactivity with cows, goat, and sheep milk secondary to homology between these proteins . 90% children allergic to cow’s milk will be reactive to goat’s milk on oral food challenge
75% of cow’s milk allergic children will tolerate extensively heated cow’s milk (e.g. baked goods)
1-2% children Yolk considered less allergenic than white Egg white has 23 glycoproteins 70% egg allergic children may be able to ingest small amounts of egg protein in extensively heated (baked) products 0.4% children Belongs to legume family with peanut . 88% have concomitant peanut allergy
1.1% Most common food allergy in pediatric population beyond 4 years of age Most likely to cause fatalities 21.5% chance of outgrowing peanut allergy 8% risk of recurrence 0.6% population allergic Walnuts – 34% Cashews – 20% Almonds – 15% Pecan – 9% Pistachio – 7% Hazelnut, Brazil nut, Pine Nut, Macadamia nut < 5%
In recent study, 12% patients allergic to more than 1 tree nut Approximately 30-50% of peanut allergic patients have at least one tree nut allergy Approximately 9% outgrow tree nut allergy . Note 14/19 patients who never ingested tree nuts but had elevated specific IgE passed the oral food challenge . Of these 14 patients, 58% with specific IgE ≤ 5 passed the oral food challenge while 63% with specific IgE ≤ 2 passed the oral food challenge
Fleischer DM. J Allergy Clin Immunol. 2005;116(5):1087-93
The severity of a reaction cannot be accurately predicted by the degree of severity of past reactions and depends on: Amount ingested Food form (cooked, raw, or processed) Co-ingestion of other foods
The severity also may be influenced by The age of the patient The degree of sensitization at the time of ingestion The rapidity of absorption, based on whether . The food is taken on an empty stomach . The ingestion is associated with exercise . The patient has other co-morbid conditions (e.g., asthma or AD )
1% to 20% Typically occur 8 hours after initial reaction, but up to 72 hours later Up to 25% of fatal or near-fatal food reactions There is no consensus on optimal observation time following the initial reaction; recommendations range from 4 to 24 h Minimum 4 hour observation Studies suggest that delayed administration, inadequate dosing, or a need for large doses of epinephrine are risk factors for biphasic reactions Also failure to administer corticosteroids also seems to predispose towards biphasic reaction
ImmunoCAP – Allergy blood tests* . Generally felt to be less sensitive than SPT [+] Allergen kUA/L PPV Egg 7 98 Infants ≤2 yr[ ] 2 95 ∗ Milk 15 95 Infants ≤1[ ] 5 95 ∗∗ Peanut 15 99 Fish 20 95 Soybean 30 73 Wheat 26 74 Tree nuts[ ] ≈15 ≈95 *Results from ImmunoCAP∗∗∗ testing are not comparable to IgE levels from other assay systems such as Immunolite and Turbo-MP. Must know assay lab using.
Airway, Breathing, Circulation Vital signs EpiPen Concurrently, call 911 Supine position with legs elevated (unless respiratory compromise or vomiting) Supplemental O2 . Optimize organ perfusion and bronchodilates IVF Weight estimation for dosing of medications What are the indications to give Epinephrine? . Severe reaction . Respiratory distress . Swollen throat . Loss of Consciousness
Seconds but is rapidly metabolized Effect often short-lived and repeat doses may be necessary for severe or protracted anaphylaxis (within 1-2 minutes if first one is not working) 10-20% of anaphylactic cases required 2nd Epipen injection . Jarvinen et al. J Allergy Clin Immunology 2008; 122:133-138 Second line treatment only Not life-saving Only relieve itching and urticaria Do not relieve stridor, shortness of breath, wheezing, GI symptoms, or shock Onset of action 20-60 minutes H1 and H2 antagonism superior to H1 alone
National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010
Prolonged observation is mandated At least 8-24 hours after symptoms have resolved . Moderate to severe reaction . Asthmatic wheezing . Ingested antigen with risk of systemic absorption . Previous history of biphasic response Strict Avoidance of Allergenic Foods . Regular growth monitoring . Nutritionist ▪ Possibly decreases risk of malnutrition (e.g. Ca, Vit D) ▪ Christie et al. J Am Diet Assoc 2002; 102(11): 1648-51. ▪ Education on how to read labels . Only 7%, 22%, and 54% of parents correctly identified labeled products containing milk, egg, and peanut respectively . Joshi et al . J Allergy Clin Immunol 109(6): 920-2. ▪ Food Allergen Labeling and Consumer Protection Act (FALCA) effective 2006 mandates manufacturer disclosure of the most common allergens (milk, egg, wheat, soy, peanut, tree nuts, fish, and crustacean shellfish) in plain English in the ingredient list or in a separate “contains” statement ▪ 17% of 20,214 products contain advisory labels Pieretti, J Allergy Clin Immunol 2009;124:337-41
Strict Avoidance of Allergenic Foods . Nutritionist ▪ Education on how to read labels ▪ Food allergic patients assume incorrectly that terms such as ‘‘shared equipment,’’ ‘‘shared facility,’’ or ‘‘may contain’’ indicate different levels of risk. ▪ Avoid products that state “may contain” or “manufactured on equipment” ▪ 5-17% risk of significant amount of allergen in food ▪ 1.9% without declaration of allergen contained allergen - Remington et al. J Allergy Clin Immunol 2010;125 (2): AB218 - Ford et al. J Allergy Clin Immunol 2009; 123 (2): S176
Even when patients ask about ingredient information they may receive inaccurate information If symptoms start assume allergic reaction, call for help . Bock S.A. Academy of Allergy Asthma and Immunology Annual meeting 2009
. Food Allergy and Anaphylaxis Network (www.foodallergy.org) ▪ Newsletter ▪ Website with patient handouts, educational videos and children’s books
Epinephrine . 1st line treatment . Life-saving . Majority of patients who have prescription do not carry Epinephrine . Even those who carry the Epinephrine do not administer the medication when clinically indicated ▪ Only 3% of patients who died of food anaphylaxis had Epineprhine ▪ Bock et al. J Allergy Clin Immunol 2001;107:191-3 . Only 21% of families demonstrate proper use ▪ Sicherer, et al. Pediatrics 105 (2000), pp. 359–362
. Must demonstrate how to use it . Have families practice . Watch Training Video (EpiPen or TwinJect)
While administering epinephrine, call 911 Delayed administration of epinephrine has contributed to fatalities . Give Epinephrine immediately, but at least within 30 minutes, of food allergic reaction ▪ Sampson et al. Engl J Med. 1992. 327(6):380-4. All other medications, including antihistamines and corticosteroids considered adjunctive . Antihistamine use most common reason cited for not using Epinephrine and may significantly increase risk of life-threatening reaction ▪ Simons et al. J Allergy Clin Immunol 2009;124:301-6 Liquid Zyrtec or Benadryl at all times . Prefilled teaspoons are easy to transport and readily available over the counter
Medicalert.org laurenshope.com
Inscription example: “Patient’s name. Allergic to peanuts, tree nuts + Asthma. Give EpiPen and call 911. Mother or father: cell phone number.” MMR and Varicella and influenza grown in chicken-embryo fibroblast culture and contains minimal amounts of egg protein Can be administered safely in egg-allergic patients, even those with a severe h/o allergic reaction if skin test is negative
National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010
History: symptoms, timing, reproducibility . Acute reactions vs chronic disease Diet details / symptom diary . Specific causal food(s) . “Hidden” ingredient(s) Physical examination: evaluate disease severity Identify general mechanism . Allergy vs intolerance . IgE versus non-IgE mediated
Suspect IgE-mediated . Prick skin tests (fresh extract if oral allergy) . RAST Suspect non-IgE-mediated . Consider biopsy of gut, skin Suspect non-allergic, consider: . Breath hydrogen . Sweat test . Endoscopy Positive prick test or RAST . Indicates presence of IgE antibody NOT clinical reactivity Negative prick test or RAST . Essentially excludes IgE antibody (>95%) ID skin test with food . Risk of systemic reaction & not predictive . Contraindicated Unproven/experimental tests . Provocation/neutralization, cytotoxic tests, applied kinesiology, hair analysis, IgG4 Recommended Interpretation of Food Allergen-Specific IgE levels (kU/L)
Egg Milk Peanut Fish Soy Wheat
Reactive if > 7 15 14 20 65 80
Possibly reactive 30 26 (physician challenge) Unlikely reactive if < 0.35 0.35 0.35 0.35 0.35 0.35 (home challenge)
* Sampson, H. Utility of food specific IgE in predicting symptomatic food allergy. JACI. 2001. Elimination diets (1 to 6 weeks) . Eliminate suspected food(s), or . Prescribe limited “eat only” diet, or . Elemental diet Oral challenge testing (MD supervised, ER meds available) . Open . Single-blind . Double-blind, placebo-controlled (DBPCFC) Test for specific-IgE antibody . Negative: reintroduce food* . Positive: start elimination diet Elimination diet . No resolution: reintroduce food* . Resolution ▪ Open / single-blind challenges to “screen” ▪ DBPCFC for equivocal open challenges
* Unless convincing history warrants supervised challenge Includes disease with unknown mechanisms . Food additive allergy Elimination diets (may need elemental diet) Oral Challenges . Timing/dose/approach individualized for disorder ▪ Enterocolitis syndrome can elicit shock ▪ Enteropathy / eosinophilic gastroenteritis may need prolonged feedings to develop symptoms . DBPCFCs preferred . May require ancillary testing (endoscopy / biopsy) If Specific IgE to a food > 25 kU/L., low likelihood of losing allergy Component Diagnostic Testing and Epitope Arrays are moving forward to further our knowledge and diagnostics capabilities There are no reliable predictors to determine whose food allergy will persist There are no reliable predictors to determine whose food allergy will lead to severe anaphylaxis (predicted in 50% of cases of food allergy) The gold standard to identify an offending food allergen is a double blind, placebo-controlled in vivo challenge which requires hospitalization, is costly, lengthy and can result in an anaphylactic shock Once the tests occur, there are many false positives that can lead to elimination diets in children associated with malnutrition (NY Times.2009)
Epitope Arrays : Development of a novel peptide microarray for large-scale epitope mapping of food allergens
Serum dilution experiment (A) and peptide inhibition assay (B). Areas showing non-specific binding are indicated with black arrows. Targeted peptides, which are the peptides pre-incubated with the serum pool are indicated with red arrows for each inhibition group. Areas with possible cross- inhibition based on sequence alignment are indicated with blue arrows.
J Allergy Clin Immunol. 2009 Aug;124(2):315-22. Lin J, et al. New Diagnostic Allergy Test based on rapid assessment of blood basophil activation
Stimulated by Antigen
Unstimulated Expression of molecules on the cell surface (expressed by cytoplasmic compartments) for example CD203c or CD63 New Diagnostic Allergy Test Based on rapid assessment of blood basophil activation
Spin 300 x g Non Activated-diluent Antibodies 0 Breaks Activated-allergen 1. Anti-CD203c 20 minutes incubation 2. Anti-CD63 3. Anti-CD123 Plasma 4. HLA-DR Leukocytes Abs Wash, Gradient Staining and Flow RBC Abs diluted in Cytometry 1% BSA
0.05% NaN3 in PBS TIME To RESULT: ~ 1 HOUR •Responses to multiple allergens can be tested at the same time (to assess which are most important in that patient) •Results available within 1 hour •Use the finger stick test to determine who can tolerate their next dose of food oral immunotherapy Our Diagnostic Allergy Test Can Detect Allergic vs. Non-allergic Patients
1000 Non Activated 750 basophils 500
CD203c (MFI) 250
0 Peanut allergic Controls Activated basophils B A 4 4
3 3
2 2 r2=0.81 1 1 r2=0.81
0 0 Modified Bock's Reaction GradeModified Modified Bock's Reaction GradeModified 0 100 200 300 400 500 0 100 200 300 400 CD203c MFI CD63 MFI Hidden ingredients (peanut in sauces or egg rolls) Labeling issues (“spices”, changes, errors) Cross contamination (shared equipment) “Code words” (“Natural flavor” may be CMP) Seeking assistance . Registered dietitian: (www.eatright.org) . Food Allergy Network (www.foodallergy.org; 800- 929-4040)
Artificial butter flavor, butter, butter fat, buttermilk, casein, caseinates (sodium, calcium, etc.), cheese, cream, cottage cheese, curds, custard, Half&Half®, hydrolysates (casein, milk, whey), lactalbumin, lactose, milk (derivatives, protein, solids, malted, condensed, evaporated, dry, whole, low-fat, non-fat, skim), nougat, pudding, rennet casein, sour cream, sour cream solids, sour milk solids, whey (delactosed, demineralized, protein concentrate), yogurt. MAY contain milk: brown sugar flavoring, natural flavoring, chocolate, caramel flavoring, high protein flour, margarine.
* It is common to have a reaction to a hidden ingredient to rather than to have an allergic reaction to a previously tolerated food.
Soy (confirm soy IgE negative) . <15% soy allergy among IgE-CMA . ~50% soy allergy among non-IgE CMA Cow’s milk protein hydrolysates . >90% tolerance in IgE-CMA Partial hydrolysates . Not hypoallergenic! (ex/ Nutramigen) Elemental amino acid-based formulas . Lack allergenicity (ex/ Neocate)
* CMA=cow’s milk allergy Epinephrine: drug of choice for reactions . Self-administered epinephrine readily available . Train patients: indications/technique Antihistamines: secondary therapy Emergency plan in writing . Schools, spouses, caregivers, mature sibs / friends Emergency identification bracelet Re-evaluate for tolerance periodically Interval and decision to re-challenge: . Type of food allergy . Severity of previous symptoms . Allergen Ancillary testing . Skin prick test/RAST may remain positive . Reduced concentration food specific-IgE encouraging Aimed at “high risk” newborn . Positive family history: biparental or parent / sib Breast feeding generally protective of allergy Wean / supplement with extensively hydrolyzed hypoallergenic protein hydrolysate Delay introduction of solid foods > 6 mo . Cow milk/dairy: 6-12 months . Egg: 12-24 months . Peanut, tree nut, seafood > 24-48 mo Identification of causative food Institution of elimination diet Education on food avoidance Development of action plan Prevention of other allergies History and physical paramount IgE & non-IgE mediated conditions exist Diagnosis by elimination and challenge Avoidance/education/preparation for emergencies are current therapies Periodic re-challenge to monitor tolerance as indicated by history, allergen, and level of food specific-IgE Review several new forms of allergen immunotherapy Discuss positive and negative findings of their use in clinical trials and argument if they might become available in the future Discuss the usefulness of immunotherapy in food allergy and the current status of these investigations
Recombinant anti-IgE antibody (Stanford) Gene (naked DNA) immunization with CPG repeats (Johns Hopkins) Sublingual Immunotherapy (Stanford) Oral Immunotherapy (Stanford) Hypo-allergenic formulas (Stanford) Probiotics (UCSF) Background BACKGROUND
There is no effective, FDA-approved treatment for food allergy, except to avoid the offending foods and to have ready access to self-injectable epinephrine. Recently, oral desensitization has been used to treat patients with food allergy; the process is slow and associated with frequent allergic reactions. OIT (multi or single)---4-55 yrs . Milk, Wheat, Egg, Peanut, Tree Nut, Sesame Seed, and/or Soy Recombinant anti-IgE antibody + OIT---4-55 yrs Sublingual Immunotherapy (peanut only)---5-21 yrs Skin patch (peanut only)---5-21 yrs Chinese Herbal Medicine---5-21 yrs Recombinant/Engineered protein allergens Peanut OIT- 12 mo to 48 mo Lactobacillus (genetically modified)---Phase I Denatured/baked milk vs non baked milk---5-21 yrs Highly cooked egg vs less cooked egg---5-21 yrs Oral Immunotherapy Study Design
Provided by Dr. Wesley Burks of Duke University *
Inclusion Criteria: . Age >4 yrs age . Symptomatic food allergy sensitivity include positive skin prick testing (greater tha n 8 mm) and specific IgE > 7 kU/L. . Medically documented history of near fatal reaction to food in- gestion . Positive DBPCFC . Allowed to take antihistamines, asthma meds, and nasal steroid s as indicated for symptomatic control of atopic conditions Exclusion Criteria: . No significant organ system disease . Failure to comply with training for allergy reactions . FEV1 or PEF is <80% predicted with or without meds . Subjects taking oral, IM,IV steroids, beta blockers. * Similar to Duke and Arkansas Screening period is very important Preliminary Dosing Visit: Incremental escalating doses of fod flour given orally as tolerated to a max of the top dose of allergen of 6 mg (as per Duke and Arkansas protocol). Up dosing visits weekly to MTD (awareness of symptoms) Treatment Course: Top dose (“ maintenance dose”) self administered daily for minimum of 12 months Blood samples minimally should be collected at baseline, 6 months, 12 months, continuing Role of Adjunctive therapy in OIT: Use of Anti IgE in reported studies as example
AAAAI, 2011 Savage, et al. Omalizumab In Peanut Allergy: Effects On The Basophil, Mast Cell, And Food Challenge Response . N=10 Peanut-allergic adults with 6 mos of omalizumab. At a median of 5 weeks, a DBPCPC was performed in 9 subjects. Results: “There was a significant increase in the mean dose of peanut protein tolerated (DPP, 212 mg to 6,010 mg,p<0.01)”
AAAAI, 2011 Pena-Peloche, et al. Treatment Of Severe And Persistent Food Allergy With Omalizumab . Milk and egg allergic children underwent 16 weeks of omalizumab. Out of seven patients, 2 patients showed improvement on food challenge, 3 patients went forward with OIT.
JACI, 2011 Sampson, et al. A phase II, randomized, double-blind, parallel-group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. - 14 subjects reached primary endpoint (n=9 Xolair and n=5 placebo) and comparing change from baseline in maximum tolerable peanut dose after 24 wks of treatment, there appeared to be a greater shift in peanut tolerability in subjects treated with omalizumab (44%) vs placebo (20%).
NEJM, 2003 Leung, D. et al. Effect of anti-IgE therapy in patients with peanut allergy . A double-blind, randomized, dose-ranging trial in 84 patients. A 450-mg dose of TNX-901 increased the threshold of sensitivity to peanut on oral food challenge from 0.5 to 9 peanuts.
Allergy Asthma Proc. 2010 Rafi, et al. Effects of omalizumab in patients with food allergy. . Assessed the efficacy of omalizumab in 22 patients with persistent asthma and concomitant IgE- mediated food allergy with improvement on reexposure to sensitized foods. CURRENTLY ONGOING ANTI – IGE AND FOOD ORAL IMMUNOTHERAPY STUDIES
- Milk OIT + omalizumab in milk allergic subjects (7-35 yrs) ▪ PI, Dr. Hugh Sampson . Peanut OIT + omalizumab study in peanut allergic patients (>12 yrs) ▪ PI, Dr. Wesley Burks . Peanut OIT + anti IgE in peanut allergic subjects (>18 yrs) ▪ Novartis . Peanut OIT + omalizumab in peanut allergic subjects (7-25 yrs) ▪ PI, Dr. Dale T. Umetsu . Multi OIT + omalizumab in tree nut, milk, egg, and/or peanut allergic subjects (4-55 yrs) ▪ PI, Dr. Kari Nadeau
Source: clinicaltrials.gov
Mechanisms of Anti IgE Therapy
IgE
Anti-IgE Anti-IgE
FcεRI receptor
Mast cell
Monoclonal anti-IgE antibodies, like omalizumab, selectively bind to the Cɛ3 domain of IgE with high affinity. Each IgE molecule has two antigenic sites for anti-IgE, and so can be bound by two drug molecules simultaneously. These form small, soluble, biologically inert IgE/anti-IgE complexes that are easily cleared from the circulation. Possible historical comparisons: Cow’s milk OIT with no omalizumab Anti IgE Studies in Food Allergy at Stanford (example)
Study Patient Population Methods Results
Yu et al. (2009) 5 pts (5- 25 yrs) with Pilot study using Free IgE anti-peanut decreased (from mean of peanut allergy; omalizumab every 2-4 119.4 kUa/L to 5.9 kUa/L) within 4-12 wks of positive peanut SPT (≥ wks (dosing based on treatment. One pt developed a negative peanut 8mm wheal) or serum- wgt/IgE level per SPT at 4 wks and was able to tolerate 5 gms of specific IgE (peanut product insert); no peanut in DBPCFC. IgE ≥15kUa/L) placebo Iyengar et al. 8 patients (4-22 yrs) Pilot phase I study Clinical effect not markedly different (likely due (2008) with food allergy and using higher dosing to very high serum total IgE); TARC, TSLP, and severe refractory AD frequency of OX40 ligand reduced (60-80% in 3/4 pts; 50-75% omalizumab for and 70-80% in 4/4 pts, respectively) and IL-10 higher IgE levels levels increased 80-100% in treatment group (<3,000 IU/ml; mean=1,068 IU/ml) and 1:1 placebo Nadeau et al 11 children (7-17 years) Pilot phase I study 9/10 patients reached 1000-mg dose during one- (2011) with cow’s milk allergy; using omalizumab day desensitization period; 9/10 patients milk-specific IgE (starting 9 wks before) reached the max 2000 mg daily dose by wk 16; (median 50; range rapid oral milk All 9 pts passed DBPCFC 8 wks after last dose 41.6-342 kUA/L), desensitization to (wk 24) during which cumulative dose of 7250 positive milk SPT 1000-mg; wkly dose mg (or 220 mL milk) given. All 9 pts continued (median 20/50 mm; increase over next 7- daily milk >8000 mg/day after DBPCFC; range, 11-45/20-52 12 wks reactions (mostly local and GI) occurred at mm), approx. 1% StudyPhase design: I single center study using AntiIgE Schematicwith milkof Clinical oral Study: immunotherapy
Baseline visit Start omalizumab (wk 0) Week 0-9
Desensitization (1000 mg milk powder dose, Week 9 2000 mg cumulative)
Weekly up dosing and continued omalizumab Week 9-16, escalation Maintain daily milk dose at home phase Off omalizumab Maintenance dose was 2000 mg Week 16-24
DBPCFC* Week 24-27
Home daily milk ≥ 8 oz Week 24-52
*DBPCFC=double blind placebo controlled food challenge
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011 Subject CharacteristicsSummary of Demographics
11 patients with histories of acute reactions to uncooked and cooked milk (recruited at 2 study sites). ◦ Subjects with prior history of eosinophilic GI diseases, immunotherapy, severe asthma, and/or history of intubation were excluded. Mean age: 10 years (median 8 years). Mean skin test to milk: 22 mm wheal (median 20 mm). Mean milk specific IgE: 98 kU/L (median 50 kU/L). Mean total IgE: 701 kU/L (median 349 kU/L).
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011 Results Efficacy Results
One-day desensitization to 1,000 mg (cumulative dose=2,000 mg of milk) • 7 out of 11 patients passed. • One drop out after first day of desensitization. After up to 7-11 additional wks, 9 out of 10 subjects reached an oral daily dose of 2,000 mg (primary endpoint)
At 24-27 wks, DBPCFC to 3,000 mg (cumulative dose 7,200 mg) • 9 out of 10 patients passed. After passing DBPCFC, 9 patients began tolerating 8-12 oz milk/day (including ice cream, pizza, yogurt) the next day.
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011 Results: Overall Safety Data Total number of subjects=11 Safety Results
Milk doses per child, mean (range) 209 (36-334) Total doses 2301 No. of reactions per child, mean Symptom/treatment No. (%) of total doses (range) Total reactions 41 (1.8%) 3.7 (1-7) Grade 1 (Mild) symptoms 29 (1.3%) 2.6 (1-5) On rush desensitization day 14 During weekly dose 10 escalation phase During maintenance dosing 5 Grade 2 (Moderate) symptoms 8 (0.3%) 0.7 (0-2) On rush desensitization day 5 During weekly dose 1 escalation phase During maintenance dosing 2 Grade 3 (Severe) symptoms 4* (0.1%) 0.3 (0-1) On rush desensitization day 2 During weekly dose 1 escalation phase During maintenance dosing 1 Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011 Summary CLINICAL CONCLUSIONS
This study is the first published study to use omalizumab in combination with oral desensitization. 9 of 11 patients with milk allergy treated with omalizumab and oral milk desensitization achieved the primary objective, and tolerated desensitization to a dose of 2,000 mg/day within 7-10 wks. The 9 patients then passed a DBPCFC, and began tolerating >240 ml (>8 oz) of milk/day in their diet. These results suggest a potential value for using omalizumab during rapid oral desensitization for food allergy.
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011 SummarySAFETY OIT: CONCLUSIONS
There is no cure at the current time. Drop out rates during clinical OIT studies are 15-25% Although most reactions are mild, up to 4% have been reported to be severe (requiring epinephrine). Most allergic reactions occur during home dosing Patients and families must be frequently educated Random allergic reactions can occur 3-4 years after OIT was begun. Viral infections, temperature, other allergies, exercise, menstruation—all can modulate the threshold for an allergic reaction during ingestion of food therapy Reaction medications must still be available at all times Possible mechanisms of Oral Immunotherapy
Incorvaia, et al. 2008, Antunez, et al. 2008, Aslam, et al 2010, Frew, 2010, Jutel, et al. 2006, Jones, et al. 2009, Adkis and Adkis, 2009 Nadeau and Umetsu, 2011 Why study mechanisms of OIT?
Provides our field with new targets for . Therapy (ie. peptide vaccine based in recognized epitopes in T cells) . Diagnostics (ie. basophil activation) . Prognostics (ie. following epitope arrays and inhibitory assays) Identifies predictive biomarkers in samples for successful and safe clinical outcomes (ie. Treg epigenetics? Basophil threshold studies?) Defines biological parameters for improved, customized, patient-focused therapy (dose amount, dose frequency, initiation and termination of therapy, adverse event frequency)
OIT Study Summary Results
• OIT could be promising HOWEVER • It must be considered experimental and in its early phases • There is still much to learn as to dosing and frequency and length of time on therapy • SAFETY is paramount • Work with appropriate regulatory agencies and institutional boards • Trained staff should perform DBPCFCs and DEs in a hospital setting • Patients and their families must be trained and frequently retrained • Constant (i.e. 24/7) availability of trained staff, short term and long term follow up are important. • OIT IS NOT READY FOR CLINIC USE
Identification of causative food Institution of elimination diet Education on food avoidance Development of action plan Prevention of other allergies History and physical paramount IgE & non-IgE mediated conditions exist Diagnosis by elimination and challenge Avoidance/education/preparation for emergencies are current therapies Periodic re-challenge to monitor tolerance as indicated by history, allergen, and level of food specific-IgE Stanford Alliance For Food Allergy Research
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