1	Food Allergy Leo Galland M.D. Foundation for Integrated Medicine
2	HOW PREVALENT IS FOOD ALLERGY/INTOLERANCE? 33% of 1000 teachers (56% response rate) reported avoidance specific foods because of “unpleasant” physiological reactions. A poll of 5000 US physicians on prevalence of food allergy (14% response rate): 0-80% (mean 10%)
3	Immunologic Mechanisms of Food Intolerance Type I (IgE mediated, TH2 promoted) Type II (IgG and complement mediated, cytotoxic, TH1 promoted) Type III (IgG immune complex mediated, TH1 promoted) Type IV (cell-mediated, TH1 promoted)
4	Non-immunologic Mechanisms of Food Intolerance Digestive (e.g., lactase deficiency) Pharmacologic (e.g., caffeine, ethanol) Biochemical (histamine, tyramine, salicylates, sulphites, MSG) Non-specific mast cell degranulation Lectin-mediated glycoprotein agglutination
5	Poor Sulphoxidation and Food Allergy (Scadding 1988) 74 adults with non-IgE food allergy diagnosed by elimination and challenge 78% slow carbocisteine sulfoxidizers vs 33% of controls (p<0.005) Carbon oxidation (debrisoquine): normal Theory: altered metabolism of food chemicals toxic/immunogenic metabolites by novel pathways
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7	FOOD ALLERGY/INTOLERANCE: WELL-DOCUMENTED MANIFESTATIONS Pediatric Enteropathies Celiac Disease Protein-losing Enteropathy Failure to thrive Crohn’s Disease (exacerbation) Migraine headches Migraine-associated Epilepsy ADHD Nephrotic Syndrome Allergic Arthritis Rheumatoid Arthritis (exacerbation) Atopic Eczema Allergic Rhinitis, Asthma Anaphylaxis, Angioedema, Urticaria Oral Allergy Syndrome (Ortolani) Aphthous Ulceration Alveolitis, Hemosiderosis Infantile Colic Vomiting, Diarrhea, Abdominal Pain Irritable Bowel Syndrome Hematochyzia, Colitis
8	FOOD ALLERGY IN PEDIATRIC ATOPIC ECZEMA 25-60% are food reactive Increased gut permeability at baseline after food challenges blocked by cromolyn Histamine release Circulating immune complexes Multi-system reactivity in 2/3 49% gastrointestinal 23% rhinitic 17% asthmatic Poor correlation between food responses and prick tests, RAST: milk, egg, citrus, additives, nuts, fish, wheat, tomatoes, lamb, chicken, soy
9	FOOD ALLERGY IN PERENNIAL RHINITIS (Ortolani et al) 210 patients over 1 year 3-week oligoantigenic diet 52 improved (24.8%) 28 IgE mediated (13.3%), based upon correlation with RAST, skin testing 24 no correlation
10	FOOD ALLERGY IN RECURRENT APHTHOUS STOMATITIS Cytotoxic lymphocytes/antibodies Histamine release to foods (23/60) 30% correlation of HR and ulcers Gluten, milk, food additives
11	FOOD ALLERGY IN HYPERKINETIC SYNDROME (Egger et al, Lancet 1985) 76 children seen on referral (60 boys, 16 girls) age 2-15 (mean 7.3) 37 from dysfunctional families 4 weeks’ oligoantigenic diet 2 meats, 2 starch sources, 2 fruits, 1 vegetable, calcium, multivitamin
12	RESPONSE TO OLIGOANTIGENIC DIET IN HYPERKINETIC SYNDROME Pre-diet Diet Total number 76 76 Hyperactivity: Normal 0 21 Mild 6 28 Moderate 31 19 Severe 39 8 Conners’ score 24 12 Antisocial acts 32 13 Headache 48 9 Seizures 14 1 Abdominal pain 54 8 Limb pain 33 6 Eczema, rash 29 9 Aphthous ulcers 15 5 Atopic (prick test) 30 (39%)
13	Summary of Egger’s Results Open trial: 82% of children responded favorably to the oligoantigenic diet DBPCT: 28 participated, with rating of response by parents, a neurologist and a psychologist DBPCT: 51-74% of the food intolerances confirmed
14	FOODS PROVOKING HYPERACTIVITY IN DOUBLE-BLIND, PLACEBO-CONTROL TRIAL % REACTIVE Additives 79 Soy 73 Milk 64 Chocolate 59 Grapes 50 Wheat 49 Oranges 45 Cheese 40 Eggs 39 Peanuts 32 Corn 29 Fish 23 Oats 23 Melon 21 Tomato 20
15	Cognitive-Emotional Symptoms and Food Allergy (King, 1981) DBPCT: 30 adults, 28 food extracts, sub-lingual, multiple measures, 2 judges Symptoms associated with allergen exposure: anxiety, depression, brain fog, irritability, detachment, euphoria; pruritus, cold hands, myalgia, nasal congestion, tinnitus, fatigue, headache Occurrence p=0.001, Severity p=0.002
16	FOOD ALLERGY IN PEDIATRIC MIGRAINE (Egger, 1983) 88 children, oligoantigenic diet 93% cleared by 2 weeks 90% relapsed on open challenge 40 of these, DBPC TRIAL 26 confirmed (4 reacted to placebo, 8 reacted to neither) Atopy 55%, 46% hyper, 16% seizures Milk, egg, chocolate, orange, wheat benzoate, cheese, tomato, tartrazine, rye, fish, pork, beef, corn, soy, tea
17	MIGRAINE-ASSOCIATED SYMPTOMS AND FOOD INTOLERANCE 88 PATIENTS Pre-diet Diet Abdominal pain, diarrhea 61 8 Hyperactivity 41 5 Limb pain 41 7 Rhinitis 34 15 RAS 15 2 Vaginal discharge 11 1 Asthma 7 3 Eczema 6 3 27/40 provoked by DBPC food trial 10/40 provoked by placebo also 3/40 provoked by neither
18	EVIDENCE FOR ALTERED IMMUNE ACTIVATION IN RESPONSE TO FOODS IN MIGRAINE (Marteletti 1991, Acta Neurologica) Increased circulating immune complexes Increased activated T cells and total T cells Increased plasma IL-2 levels Effective prophylaxis with oral sodium cromoglycate
19	Food Allergy in Idiopathic Nephrotic Syndrome Basophile histamine release test + - 65% of 34 patients - 5% of 19 controls wheat, beef, milk, egg, pork 26 patients with refractory nephrosis - 6 remitted on oligoantigenic diet
20	TM, a 26 old woman with massive proteinuria, anasarca Prior: aesthetician, applying artificial nails, developed asthma, multiple inhalant allergies, provoked by allergy immunotherapy Severe anasarca emergency hospitalization, furosemide, steroids Proteinuria 4 gm/day, serum albumen 1.3 gm/L, marked hyperlipidemia, normal biopsy Required prednisone 20 mg/day maintenance
21	TM, a 26 old woman with massive proteinuria, anasarca Initial evaluation: Cushingoid, 3+ proteinuria Method: modified fast, supported by a rice-based, oligoantigenic food supplement, tapering down prednisone and daily examination of urine protein by dipstick Result: clearing of proteinuria in 7 days, return of proteinuria within 24 hours of ingesting hen’s eggs Total remission for 7 years, avoids eggs
22	Food Intolerance and Rheumatoid Arthritis 5-46% of patients in various studies have exacerbation of symptoms provoked by specific foods, mostly wheat, milk, tomatoes, various additives, some confirmed with DBPC trials An 18-year open study of foods provoking pain in 100 patients found that certain spices and food additives were commonest agents
23	GLUTEN INTOLERANCE IS PREVALENT AND PROTEAN Gliadin antibodies were found in 30/53 patients with neurological disease of unknown cause (73% had abnormal small bowel biopsies) Hadjivassiliou et al, Lancet 347: 369-371 (1996) IgG and IgA gliadin antibodies occur in 2% of Italian school children Catassi et al, Lancet 343: 200-203 (1994)
24	Cow’s Milk Allergy and IDDM Children with IDDM have IgG against a peptide fraction of bovine serum albumen that cross-react with a pancreatic beta-cell surface protein Adults with recent-onset IDDM show excessive T-cell proliferation in response to beta-casein, compared to normal and auto-immune controls
25	HOW PREVALENT IS FOOD ALLERGY/INTOLERANCE? 33% of 1000 teachers (56% response rate) reported avoidance specific foods because of “unpleasant” physiological reactions. A poll of 5000 US physicians on prevalence of food allergy (14% response rate): 0-80% (mean 10%)
26	Immunologic Mechanisms of Food Intolerance Type I (IgE mediated, TH2 promoted) Type II (IgG and complement mediated, cytotoxic, TH1 promoted) Type III (IgG immune complex mediated, TH1 promoted) Type IV (cell-mediated, TH1 promoted)
27	Non-immunologic Mechanisms of Food Intolerance Digestive (e.g., lactase deficiency) Pharmacologic (e.g., caffeine, ethanol) Biochemical (histamine, tyramine, salicylates, sulphites, MSG) Non-specific mast cell degranulation Lectin-mediated glycoprotein agglutination
28	Poor Sulphoxidation and Food Allergy (Scadding 1988) 74 adults with non-IgE food allergy diagnosed by elimination and challenge 78% slow carbocisteine sulfoxidizers vs 33% of controls (p<0.005) Carbon oxidation (debrisoquine): normal Theory: altered metabolism of food chemicals toxic/immunogenic metabolites by novel pathways
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30	FOOD ALLERGY/INTOLERANCE: WELL-DOCUMENTED MANIFESTATIONS Pediatric Enteropathies Celiac Disease Protein-losing Enteropathy Failure to thrive Crohn’s Disease (exacerbation) Migraine headches Migraine-associated Epilepsy ADHD Nephrotic Syndrome Allergic Arthritis Rheumatoid Arthritis (exacerbation) Atopic Eczema Allergic Rhinitis, Asthma Anaphylaxis, Angioedema, Urticaria Oral Allergy Syndrome (Ortolani) Aphthous Ulceration Alveolitis, Hemosiderosis Infantile Colic Vomiting, Diarrhea, Abdominal Pain Irritable Bowel Syndrome Hematochyzia, Colitis
31	FOOD ALLERGY IN PEDIATRIC ATOPIC ECZEMA 25-60% are food reactive Increased gut permeability at baseline after food challenges blocked by cromolyn Histamine release Circulating immune complexes Multi-system reactivity in 2/3 49% gastrointestinal 23% rhinitic 17% asthmatic Poor correlation between food responses and prick tests, RAST: milk, egg, citrus, additives, nuts, fish, wheat, tomatoes, lamb, chicken, soy
32	FOOD ALLERGY IN PERENNIAL RHINITIS (Ortolani et al) 210 patients over 1 year 3-week oligoantigenic diet 52 improved (24.8%) 28 IgE mediated (13.3%), based upon correlation with RAST, skin testing 24 no correlation
33	FOOD ALLERGY IN RECURRENT APHTHOUS STOMATITIS Cytotoxic lymphocytes/antibodies Histamine release to foods (23/60) 30% correlation of HR and ulcers Gluten, milk, food additives
34	FOOD ALLERGY IN HYPERKINETIC SYNDROME (Egger et al, Lancet 1985) 76 children seen on referral (60 boys, 16 girls) age 2-15 (mean 7.3) 37 from dysfunctional families 4 weeks’ oligoantigenic diet 2 meats, 2 starch sources, 2 fruits, 1 vegetable, calcium, multivitamin
35	RESPONSE TO OLIGOANTIGENIC DIET IN HYPERKINETIC SYNDROME Pre-diet Diet Total number 76 76 Hyperactivity: Normal 0 21 Mild 6 28 Moderate 31 19 Severe 39 8 Conners’ score 24 12 Antisocial acts 32 13 Headache 48 9 Seizures 14 1 Abdominal pain 54 8 Limb pain 33 6 Eczema, rash 29 9 Aphthous ulcers 15 5 Atopic (prick test) 30 (39%)
36	Summary of Egger’s Results Open trial: 82% of children responded favorably to the oligoantigenic diet DBPCT: 28 participated, with rating of response by parents, a neurologist and a psychologist DBPCT: 51-74% of the food intolerances confirmed
37	FOODS PROVOKING HYPERACTIVITY IN DOUBLE-BLIND, PLACEBO-CONTROL TRIAL % REACTIVE Additives 79 Soy 73 Milk 64 Chocolate 59 Grapes 50 Wheat 49 Oranges 45 Cheese 40 Eggs 39 Peanuts 32 Corn 29 Fish 23 Oats 23 Melon 21 Tomato 20
38	Cognitive-Emotional Symptoms and Food Allergy (King, 1981) DBPCT: 30 adults, 28 food extracts, sub-lingual, multiple measures, 2 judges Symptoms associated with allergen exposure: anxiety, depression, brain fog, irritability, detachment, euphoria; pruritus, cold hands, myalgia, nasal congestion, tinnitus, fatigue, headache Occurrence p=0.001, Severity p=0.002
39	FOOD ALLERGY IN PEDIATRIC MIGRAINE (Egger, 1983) 88 children, oligoantigenic diet 93% cleared by 2 weeks 90% relapsed on open challenge 40 of these, DBPC TRIAL 26 confirmed (4 reacted to placebo, 8 reacted to neither) Atopy 55%, 46% hyper, 16% seizures Milk, egg, chocolate, orange, wheat benzoate, cheese, tomato, tartrazine, rye, fish, pork, beef, corn, soy, tea
40	MIGRAINE-ASSOCIATED SYMPTOMS AND FOOD INTOLERANCE 88 PATIENTS Pre-diet Diet Abdominal pain, diarrhea 61 8 Hyperactivity 41 5 Limb pain 41 7 Rhinitis 34 15 RAS 15 2 Vaginal discharge 11 1 Asthma 7 3 Eczema 6 3 27/40 provoked by DBPC food trial 10/40 provoked by placebo also 3/40 provoked by neither
41	EVIDENCE FOR ALTERED IMMUNE ACTIVATION IN RESPONSE TO FOODS IN MIGRAINE (Marteletti 1991, Acta Neurologica) Increased circulating immune complexes Increased activated T cells and total T cells Increased plasma IL-2 levels Effective prophylaxis with oral sodium cromoglycate
42	Food Allergy in Idiopathic Nephrotic Syndrome Basophile histamine release test + - 65% of 34 patients - 5% of 19 controls wheat, beef, milk, egg, pork 26 patients with refractory nephrosis - 6 remitted on oligoantigenic diet
43	TM, a 26 old woman with massive proteinuria, anasarca Prior: aesthetician, applying artificial nails, developed asthma, multiple inhalant allergies, provoked by allergy immunotherapy Severe anasarca emergency hospitalization, furosemide, steroids Proteinuria 4 gm/day, serum albumen 1.3 gm/L, marked hyperlipidemia, normal biopsy Required prednisone 20 mg/day maintenance
44	TM, a 26 old woman with massive proteinuria, anasarca Initial evaluation: Cushingoid, 3+ proteinuria Method: modified fast, supported by a rice-based, oligoantigenic food supplement, tapering down prednisone and daily examination of urine protein by dipstick Result: clearing of proteinuria in 7 days, return of proteinuria within 24 hours of ingesting hen’s eggs Total remission for 7 years, avoids eggs
45	Food Intolerance and Rheumatoid Arthritis 5-46% of patients in various studies have exacerbation of symptoms provoked by specific foods, mostly wheat, milk, tomatoes, various additives, some confirmed with DBPC trials An 18-year open study of foods provoking pain in 100 patients found that certain spices and food additives were commonest agents
46	GLUTEN INTOLERANCE IS PREVALENT AND PROTEAN Gliadin antibodies were found in 30/53 patients with neurological disease of unknown cause (73% had abnormal small bowel biopsies) Hadjivassiliou et al, Lancet 347: 369-371 (1996) IgG and IgA gliadin antibodies occur in 2% of Italian school children Catassi et al, Lancet 343: 200-203 (1994)
47	Cow’s Milk Allergy and IDDM Children with IDDM have IgG against a peptide fraction of bovine serum albumen that cross-react with a pancreatic beta-cell surface protein Adults with recent-onset IDDM show excessive T-cell proliferation in response to beta-casein, compared to normal and auto-immune controls
48	DIAGNOSIS OF FOOD ALLERGY History atopic disease multisystem complaints fluctuations provocations - rough skin, red ears, geographic tongue Skin tests, IgE (total/food specific) Dietary elimination/challenge symptom change gut permeability change
49	D-XYLOSE ABSORPTION DECREASES AFTER FOOD ALLERGEN CONSUMPTION In children with cow’s milk protein enteropathy (diarrhea, pain), 1 hour blood d-xylose was significantly higher on a milk-free diet than 4 days after starting a milk-containing diet Morin et at, Lancet i: 1102-1104 (1979)
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51	Elimination Diets Elemental Oligoantigenic Avoid commonest allergens: milk, wheat, corn, soy, eggs, citrus, nuts, fish Gluten and/or casein-free Yeast and mold-free Low-salicylate
52	Technique of Food Elimination Obtain baseline measure of target symptoms or signs Complete avoidance of all food/drink containing test components for 5-14 days Instruct patients/parents in foods that can or should be eaten and in monitoring of symptoms
53	Food Challenge Techniques If there is no change in target parameters, return to usual diet en bloc and observe for exacerbation If improvement is observed, introduce foods singly, one every 1-2 days, 2-6 challenges for each food; delayed reactions are common If symptoms occur, hold challenges until clear Avoid suspected symptom provokers Re-challenge with these after completion
54	TREATMENT OF FOOD ALLERGY Symptomatic pharmacotherapy Dietary avoidance Pre-prandial cromolyn 800-1600 mg/day Intestinal repair Probiotics Hyposensitization by anergy induction Counseling: nutritional, psychological
55	Probiotics for Managing Food Allergy Infants with atopic eczema and cow’s milk allergy fed hydrolyzed whey formula with or without Lactobacillus GG -Clinical improvement associated with 95% decline in fecal TNF-alpha in the Lactobacillus group, signifying reduced GI inflammation Majamaa, Isolauri, J All Clin Immunol 1997
56	Probiotics for Prevention of Food Allergy in Infants DBPCT: Lactobaciilus GG given to high risk mothers during last 2 weeks of pregnancy and for 6 months after birth to their offspring Atopic eczema at 2 years Controls: 31/68 (46%) Lactobacillus 15/64 (23%), RR=0,51 Kalliomaki et al, Lancet 357: 1076-79 (2001)