Food allergy – the old and the new Cindy Salm Bauer, MD, FAAAAI Division of Allergy and Immunology, Phoenix Children's Hospital Assistant Professor, Dept of Medicine, Mayo Clinic Arizona

Disclosures • None

Objectives • Define IgE mediated food allergy compared to other adverse food reactions. • Understand the current recommendations for preventing food allergy. • Know the benefit of food challenges, including the use of baked food challenges. • Understand the current limitations to oral immunotherapy and that it is not FDAapproved.

Overview • Background – – – –

Definition Prevalence Natural Course Pathophysiology

• Diagnosis • Prevention • Treatment

Definition • IgE mediated food allergy: – An adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food

• Food intolerance: – A non-immune reaction, including metabolic, toxic, pharmacologic, and undefined mechanisms

JACI 2010;126(Suppl):S1-58

Adverse Food Reactions Immune mediated IgE mediated Acute urticaria/ angioedema, oral allergy syndrome, rhinitis, asthma, anaphylaxis, food dependent exercise induced anaphylaxis

JACI 2014;133:291-307.

Non-IgE mediated or Cell mediated

FPIES, celiac disease, dietary protein proctitis, allergic contact dermatitis

Non-Immune mediated Mixed

Atopic eczema, eosinophilic gastrointestinal disease

Metabolic

Pharmaco -logic Caffeine, tyramine

Lactose intolerance, galactosemia, EtOH intolerance

Toxic

Other

Scromboid or other food poisoning

Sulfites, food aversion, anorexia, auriculotemporal syndrome, gustatory rhintitis

Prevalence • 8 foods account for 90% of all foodallergic reactions: – – – – – – – –

cow’s milk, eggs, peanuts, tree nuts wheat, soy, fin fish, and shellfish

JACI 2010;125:S116-125.

Question #1 A 14 y/o male with a history of allergic rhinitis reports suddenly being allergic to “every food” starting the first week of April. He reports that he can’t eat pears, apples, cherries, peaches, or peanuts. Bread, rice, potatoes and meat are fine as was apple pie.

Question #1 What is his diagnosis? A. Eosinophilic Esophagitis B. Oral Allergy Syndrome C. Multiple Food Allergy Syndrome D. Eosinophilic gastritis

Answer #1 B: Oral Allergy Syndrome (OAS) – “Pollen-food syndrome” – Molecular mimicry – Symptoms may worsen in season; mild – Cooked foods tend to be tolerated – Sensitization occurs via the respiratory route – Most frequent clinical manifestation of food allergy in older children and adults

Natural Course • Persistent into adulthood – Peanut, tree nuts – Shellfish, finfish

• Resolution in childhood – Cow’s milk, egg, wheat, and soy – ~70% by 10 years – ~80% by age 16 years

JACI 2014;133:291-307, JACI 2010;125:S116-125.

Pathophysiology • Failure for the development of oral tolerance – Tolerance: a robust T cell-mediated hyporesponsiveness to antigen encountered in the gut – Recognize intestinal pathogens, commensal microbes, and food antigen – Sensitization via the oral vs. cutaneous route (bypasses tolerance induction)

Mucosal Immunology 2012;5:232–239, JACI 2012;129:1570-1578

Bauer C. Chapter 3: Specific Immune Responses. ACAAI Review for the Allergy and Immunology Boards—Second Edition. 2013 by American College of Allergy, Asthma & Immunology.

Diagnosis

http://www.alk-abello.com/US/products/diagnostics/Pages/SectionFront.aspx

Question #2 On a vacation in Florida, a 12-year-old boy orders mahi mahi in a restaurant. Within 20 minutes of eating it, he develops abdominal cramps, vomiting, swelling of the tongue, and trouble breathing. He has eaten fish all of his life. Skin testing to all white fish is negative.

Question #2 What is the cause of his illness? A. Finfish allergy B. Shellfish allergy C. Scromboid fish poisoning D. Gastroenteritis

Answer #2 C. Scombroid fish poisoning – Query if others “got sick” – Eating spoiled (decayed) fish that release histamine-like chemicals – Mackerel, tuna, bluefish, mahi-mahi, bonito, sardines, anchovies, and related species of fish

It’s often in the history. Diagnostics are supportive!!!

Diagnostics • Detailed familiarity with the gamut of foodinduced allergic disorders • Understanding of the pathophysiology (timing, symptoms, etc.)

Adverse Food Reactions Immune mediated IgE mediated Acute urticaria/ angioedema, oral allergy syndrome, rhinitis, asthma, anaphylaxis, food dependent exercise induced anaphylaxis

JACI 2014;133:291-307.

Non-IgE mediated or Cell mediated

FPIES, celiac disease, dietary protein proctitis, allergic contact dermatitis

Non-Immune mediated Mixed

Atopic eczema, eosinophilic gastrointestinal disease

Metabolic

Pharmaco -logic Caffeine, tyramine

Lactose intolerance, galactosemia, EtOH intolerance

Toxic

Other

Scromboid or other food poisoning

Sulfites, food aversion, anorexia, auriculotemporal syndrome, gustatory rhintitis

Diagnostics • Specific IgE testing – Sensitization does not necessarily imply reactivity – RAST vs. ImmunoCAP – Higher specific food IgE (and skin test size)  probability; not severity of reaction – Skin prick testing has a high negative predictive value (>90%)

JACI 2014;133:291-307.

Diagnostics • Component-resolved diagnostics (CRD) – Testing for specific protein within foods • Labile versus stable • Binding to conformational versus linear epitopes Food

Labile

Stabile

Peanut

Ara h8

Ara h1/2/3/6/9

Cow’s milk

Whey

Casein

Egg

Ovalbumin

Ovomucoid

JACI 2014;133:291-307, JACI 2010;125:S116-125

Diagnostics • What about cross reactivity? Cross contamination? Allergy to:

Related food:

Clinical Reaction Rate

Peanut

Most legumes

5%

Tree nut

Other tree nuts

35%

Fin fish

Other fin fish

50%

Shellfish

Other shellfish

75%

Grain

Another grain

25%

Cow’s milk

Goat/sheep milk Mare milk Beef

>90% 5% 10%

JACI 2014;133:291-307.

Ann Allergy Asthma Immunol 2017;118:591-596

Diagnostics • Diagnostic gold standard – Oral food challenge (OFC) • Gradually feeding a possible allergen under medical supervision to determine tolerance or clinical reactivity. • Double-blind • Placebo-controlled

JACI 2010;125:S116-125.

?

Diagnostics • Common uses for oral food challenges (OFC) – Tolerance to the food antigen • Extensively heated or “baked” food antigens – Milk and egg – Denatures conformational epitopes

JACI 2014;133:324-334.

Diagnostics • Unsafe methods – Intradermal testing • Un-useful methods – Total IgE – Atopy patch testing* • Unproven methods – Lymphocyte stimulation – Facial thermography – Gastric juice analysis

JACI 2010;126:S1-58.

– Endoscopic allergen provocation – Hair analysis – Applied kinesiology – Provocation neutralization – Allergen-specific IgG/G4 – Cytotoxicity assays – Electrodermal test (Vega) – Mediator release assay

Prevention

Question #3 • When should you consider peanut protein introduction in a child with severe eczema? A. B. C. D.

4 to 6 months 11 to 12 months 1 to 2 years old >2 years old

Answer #3 A. 4 to 6 months

Prevention • 2000 AAP • 2008 AAP • 2010 NIAID – Breast-feeding – Maternal diet restriction – “Insufficient evidence exists for delaying introduction of solid foods, including potentially allergenic foods beyond 4 to 6 months of age.”

JACI 2010;126(suupl)S1-58

• Subjects: 640 high-risk UK infants (4-11 months) • Methods: Randomized to consume peanut (6 g of peanut protein/week; equivalent to 24 peanuts or 3 teaspoons of peanut butter/week) or avoid – Challenged at age 5

NEJM 2015 Feb 26;372(9):803-13

Prevention

NEJM 2015 Feb 26;372(9):803-13

Prevention • LEAP Take home: Early consumption of peanut in high risk infants with severe eczema or egg allergy reduced the development of peanut allergy by 81%

Prevention • Effect of avoidance on peanut allergy after early peanut consumption (“LEAP-On”) • Subjects: 550 children from the LEAP trial (all assigned to avoid peanut for 1-year) • Results: – No significant change in allergy prevalence during the year of avoidance • Take home: Absence of reactivity is maintained

NEJM 2016;374:1435-1443

Prevention • Randomized trial of introduction of allergenic foods in breast-fed infants (EAT Study) • Subjects: UK exclusively breast fed infants (n=1,303 ) enrolled at 3 months and followed to 1 to 3 years of age • Methods: Randomized to consume highly allergenic foods at 3 months versus 6 months of age

NEJM 2016; 374:1733-1743

Prevention • Results: – No statistically significant difference in food allergy in the intention to treat group – Per protocol analysis suggested that early introduction reduced the risk of any food allergy (2.4% vs. 7.3%)(peanut and egg) – No episodes of anaphylaxis – ITT vs PP analysis? Feasibility?

NEJM 2016; 374:1733-1743

Prevention • 2017 NIAID Expert Panel Addendum Guidelines – 64 publications

JACI 2017;139:1

Prevention • Addendum 1: • Severe eczema, egg allergy or both – Obtain peanut IgE or skin prick test – Earliest Age of introduction: 4-6 months

JACI 2017;139:1

JACI 2017;139:1

Prevention • Editorial: – “no statistically significant relationship between the peanut [serum] IgE level and the baseline challenge outcome” – “Many babies without peanut allergy will have positive IgE test results, sometimes at high levels, and will be declared to have peanut allergy if they are not able to access the specialty care for further testing.”

JACI 2017;139:1

Prevention • 6-7 g of peanut protein/week divided in 3 or more feedings – 1 peanut kernel = 250 mg peanut protein – 2 g = 2 teaspoons of peanut butter 3x/week – 2 g = 21 pieces of Bamba

JACI 2017;139:1

Prevention • Addendum 2: • Mild to moderate eczema – Introduce peanut containing foods – Earliest Age of introduction: 6 months

JACI 2017;139:1

Prevention • Addendum 3: • No eczema or food allergy – Introduce peanut containing foods – Earliest Age of introduction: age appropriate and in accordance with family preferences and cultural preference

JACI 2017;139:1

Treatment • Avoidance!!! • Epinephrine autoinjector – EpiPen – Auvi-Q (0.3 mg, 0.15 mg, and 0.1 mg) – Generic epinephrine autoinjector – 2-pack

JACI 2014;133:291-307.

Treatment • Education – – – – – – – –

Food Cross-contamination Allergy Traveling and restaurants Schools Label reading Resources Medical ID Substitutes for food being eliminated Recognizing and treating anaphylaxis (action plan)

Question #4 • Which of the following stressors was noted in a recent study in 45% of children with food allergies? A. Bullying B. Restaurant phobia C. Limited food choices around friends D. Anxiety about epinephrine autoinjector use

Pediatrics 2013;131:e10-17.

Answer #4 A. Bullying – In most of the cases, parents were not aware – Children had lower quality of life scores and increased anxiety • With parental awareness, the quality of life was less affected

Pediatrics 2013;131:e10-17.

Question #5 • All patients with food allergy, especially peanut allergy, should be started on oral immunotherapy as soon as possible. It is an effective and safe, FDA approved treatment for food allergy. • True or False

Answer #5 • False

Treatment • Oral immunotherapy (OIT) – (Extensively heated or baked form) – Lyophilized or pure form of allergen

• Sub-lingual immunotherapy (SLIT) • Epicutaneous immunotherapy (EPIT)

Treatment • Baked egg food challenge (HealthNuts study) – Infants with oral food challenge (OFC) confirmed raw egg allergy (n=140) were offered baked egg challenges at age 1 – At age 2, raw egg OFC was repeated

JACI 2014;133:485-491

Treatment • Baked egg food challenge (continued) – Frequent ingestion increased the likelihood of tolerance

JACI 2014;133:485-491

Treatment • Baked cow’s milk food challenge – Baked milk tolerant initially were 28 times more likely to become raw milk tolerant • Compared with baked milk–reactive subjects – (P < .001) • Over the 3-year study

JACI 2011;128:125-31

Treatment • OIT for hen’s egg (CoFAR) – – – –

Randomized, DBPC trial of 55 children, 5-11 years olds Maintenance dose of 2,000 mg egg protein 75% of treatment group passed OFC at 22 months 28% of treatment group had sustained unresponsiveness at 24 months (2 months of avoidance) – Safety and quality-of-life issues • No severe adverse events were reported (oropharyngeal symptoms common) • (Eosinophilc esophagitis reported)

N Engl J Med. 2012 Jul;367(3):233-43, Allergy. 2007;62(11):1261, Ann Allergy Asthma Immunol. 2011;106(1):73.

Treatment • OIT for peanut (DEVIL study) – Randomized, DBPC trial of 40 children with peanut allergy, aged 9-36 months – Treatment group given 300 or 3000 mg maintenance dose of peanut OIT – Sustained unresponsiveness 4 weeks after OIT seen in 29 of 37 (78%) of the intent-to-treat population • 300 mg group – 85%; 3000 mg group 71%; p 0.43

– 95% of the subjects were affected by AEs that were likely related to OIT (85% mild; 15% moderate; none severe)

J Allergy Clin Immunol. 2017;139(1): 173.

Treatment • Phase 3 PALISADE Trial – Peanut ALlergy oral Immunotherapy Study of AR101 for DEsensitization – AR101 is a novel, investigational oral biologic drug – Patients ages 4–17 • 67.2% of AR101 subjects tolerated at least a 600-mg dose of peanut protein in the exit food challenge (after 6 months of 300 mg peanut protein treatment) • 4.0% of placebo patients (p