Food Allergies in Infants and Children Bonnie Proulx, APRN, PNP Pediatric Gastroenterology Children’s Hospital at Dartmouth – Manchester, NH

Quiz Which patient may have a food allergy? 3 year old with hives and vomiting 15 minutes after eating vanilla ice cream from Baskin Robbins. Child eats ice cream at home with no problems. 46 year old man with episode of syncope 1 hour after eating lobster for dinner. No other symptoms but did complain that he “just didn’t feel right”. 3 month old baby with bloody stools and failure to thrive. 15 year old with chronic, pruritic rash on buttocks and elbows. 25 year old with mouth and lip itching from apples, peaches, and cherries. Cooked fruit causes no symptoms.

Answer ALL OF THE ABOVE I chose this topic as I get asked at least 100 times a day if the child’s symptoms are from food allergies – I have many children taken to alternative health care providers and come back with laundry lists of “food allergies” so I wanted to review all the literature and be objective today to help you answer this overwhelming question and give you the how/when to evaluate.

Food Reactions IgE-mediated Food Allergy Reactions Oral Allergy Syndrome Non-IgE-mediated Food Hypersensitivity

Food Allergy Food allergy is characterized by immunologic responses to specific food proteins Prevalence is greatest in the first few years of life and declines over the first decade. Clinical manifestations of food allergy are dependent on the immunologic mechanism IgE-mediated reactions – rapid onset Non IgE – make take hours or days It is an ige response - the body is exposed to what it deems harmful – it makes an antibody against that protein and thus the next exposure will cause a reaction

Food Allergy Defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food

What It Is Not Chemical/pharmaceutical effect Caffeine: Tremor, diarrhea, cramps Tyramine (cheese): Migraines Scombroid fish poisoning (spoiled fish): histadine -> flush, pruritis, bronchospasm, tachycardia Sulfites (cheese, wine, beer, dried fruit, lettuce): bronchospasm MSG Aspartame Enzyme deficiency Lactose/fructose Malabsorption Bacterial toxin Jenny and wine reaction

Epidemiology As of 2014, 1 in 13 children has a FA About 4% of total U.S. population (12 million) has food allergy 6% of children (3 million) 3.5% of adults Food allergies in U.S. and other industrialized countries is increasing, along with other atopic diseases Peanut allergy has tripled since 1990 8 foods account for 90% of food allergy in U.S. Milk, egg, peanut, tree nuts, wheat, soy, fish, and shellfish Each year, 150-200 deaths are attributed to food-related anaphylaxis Reviewed new literature released in january 2015 –and stats still about the same – Interestingly peanut allergy has tripled since 1990 – etiology unknown Food allergies rates highest when self reported at 12% but truly approximately 3-6 % with true food testing and challenges with proven diagnostic methods

Prevalence Food Children Adults Milk 2.5% 0.3% Egg 1.3% 0.2% Peanut 0.8% 0.6% Tree Nuts 0.5% Fish 0.1% 0.4% Shellfish 2.0% You can see that milk is the most common in children but not in adults – thus many children outgrowing this with less than 1% by age 8

Why Is It Increasing? Hygiene Hypothesis Food Processing: roasted vs. boiled peanuts Topical sensitization Your guess is as good as mine The hygiene theory believes in parts that smaller families – less exposure to illnesses, over use of antibiotics sterilizing the gut and delaying introduction of solids may be contributing

Some food allergies may be “outgrown” Sometimes “outgrown” Usually not “outgrown” Eggs Milk Soy Peanuts Tree nuts Fish Shellfish

90% of food allergies are caused by a limited number of foods In Children In Adults Milk Egg Peanuts Wheat Soy Tree nuts Peanuts Tree nuts Fish Shellfish We see this in how the diet for kids with eosinophilic esophagitis are approached -

Includes immunologic and physiologic barrier Stomach acidity The gastrointestinal tract has a barrier system to protect the body from ingested antigens Includes immunologic and physiologic barrier Stomach acidity Mucin coat Gastrointestinal enzymes Immunoglobulins The gastrointestinal tract processes ingested food for absorption. It neutralizes foreign antigens and blocks them from entering the circulation. Enzymes from salivary, gastric, pancreatic and intestinal secretions, combined with mastication, gastric acid, and peristalsis, reduce ingested substances to small sugars, peptides and fats. Non-specific (mucin coat) and specific (secretory IgA) mechanisms ‘hold up' and/or block potentially harmful antigenic substances from penetrating the intestinal barrier.

Food Allergy: Natural History Most children will outgrow milk, egg, wheat and soy allergy by school age or adolescence Wheat: 29% by 4y, 56% by 8y, 65% by 12y Milk: 80% by 5y Nut, fish and peanut allergy tend to be life-long 20% of peanut allergic children outgrow peanut allergy, but 8% of these may re-sensitize These statistics have not really changed as provided by the data from Sampson et al in 2015

Children with atopic disease are more likely to have food allergies Seen in approximately 35% of children with atopic dermatitis. Moderate to Severe atopic dermatitis have 35% increased risk of food allergy This is due to the ige e mediated connection or sometime referred to as allergic triad -

IgE-Mediated Reactions: Pathophysiology Bronchoconstriction Mucous production Cough receptor Increased gastric acid secretion Increased intestinal motility Increased vascular permeability Dyspnea Wheeze Chest tightness Cough Abdominal pain/cramping Vomiting Diarrhea

IgE-Mediated Reactions: Pathophysiology Itch receptors Increased vascular permeability Tachycardia Vasodilation Hypotension Pruritis Flush Urticaria Angioedema Syncope Seizures Shock Death

IgE-mediated Food Allergy Reactions Arise when food allergens penetrate the gastrointestinal barrier, initiating the classic immediate hypersensitivity chain of events Frequently cause acute urticaria/angioedema May cause life-threatening events without cutaneous responses Signs/symptoms may occur within minutes to a couple of hours The most severe cases involve the cardiovascular and/or respiratory systems, resulting in food induced anaphylaxis

IgE-Mediated Reactions: Clinical Picture 80-90% reactions involve the skin Flush Pruritis Urticaria Angioedema 70% reactions involve the GI tract Nausea/vomiting Crampy pain Diarrhea 30-40% reactions involve the respiratory tract Cough Wheeze SOB Tightness in chest <10% reactions involve the cardiovascular system Hypotension Syncope Pre-syncope

IgE-Mediated Reactions: Clinical Picture IgE-mediated food allergy very rarely causes chronic symptoms Asthma and rhinitis can occur acutely as part of a reaction, but chronic rhinitis and respiratory symptoms in absence of other signs or symptoms of a systemic reaction are not typically due to food Chronic abdominal pain or diarrhea may be due to IgE-mediated food allergy but other causes, especially in an otherwise non-atopic patient, are much more common Chronic urticaria is rarely found to be caused by food or food additives, in spite of extensive testing

Diagnosing Food Allergy Patient history is paramount in the selection of foods for testing Consider: Types of symptom expressed Relationship between symptom onset and ingestion Time since the last reaction Quantity of suspected food ingested when symptoms occurred Activities at the time of (or prior to) symptoms

Diagnosing Food Allergy Patient history is paramount in the selection of foods for testing Skin testing is useful In vitro tests (ELISA) are recommended for pts with: Significant dermatographism Severe skin disease and limited surface area for skin testing Suspected marked sensitivities to certain foods Difficulty in discontinuing antihistamines or certain antidepressants Doctors generally start the testing process with a skin test or a blood test. The prick skin test, which is also known as the scratch test, examines the patient's reaction to a solution containing a protein that triggers allergies. The doctor places a drop of the substance on the patient's arm or back. The doctor then uses a needle to prick or scratch the skin. This allows the potential allergen to enter the patient's skin. If more than one food allergy is suspected, the test is repeated with other proteins applied to the skin. After about 15 minutes, the doctor can read the reactions on the patient's skin. If there is no reaction, the patient is probably not allergic to that food. The possibility of an allergy is indicated by the presence of a wheal, a bump that resembles a mosquito bite. The wheal signifies a positive reaction to the test. However, the test may show a false positive, which is a reaction to a food that does not cause allergies. The skin test is not appropriate for people who are severely allergic or have skin conditions like eczema. Those people are given the RAST (radioallergosorbent test). This test measures the presence of food-specific IgE in the blood. After a sample of the patient's blood is taken, it is sent to a laboratory. The sample is tested with different foods. Levels of antibodies are measured, and the reactions to different proteins are ranked. While measurement systems may vary, a high ranking indicates a high number of antibodies. Lab results are generally completed within a week. Results to this test may not be conclusive. A negative test may not have identified antibodies in the patient's blood. Positive results make it probable but not definite that the patient has allergies.

IgE-Mediated Reactions: Testing Skin Test Skin pricked through drop of purified protein extract Negative predictive value >95% Positive predictive value 50% Sensitivity >90% Specificity 50% Results available in 15-20 minutes Less expensive than laboratory testing ($16 for SPT vs. $33 for RAST) Blood test RAST test: CAP-RAST now able to give quantitative result Not as sensitive as SPT for foods for which we do not know cutoff values Can do if patient on antihistamines or if skin not clear Can be used to follow levels and predict likelihood of patient passing an oral challenge

Skin Testing A negative test strongly indicates against that food being responsible for the allergic reaction A positive test usually requires correlation with a clear positive history or with a food challenge A correct result sometimes relies on the use of fresh foods Children less than 1 year of age may have IgE mediated food allergy in the absence of positive skin tests, children less than 2 may have smaller wheals Postiive test produces a wheal within 10-20 minutes that is 3 mm or larger than the control- discussion in allergy world if size of wheal can be used as predictor for oral tolerance development of selected foods

Beware Negative igE serum testing does not necessarily rule out allergy If highly suspicious, skin or oral food challenge should be considered

Predictive value of IgE testing in positive or negative OFC results Food >95% Positive ∼50% Negative sIgE SPT sIgE SPT wheal (mm) Egg white ≥7 ≥2 if age <2 y ≥7 ≤2 ≤3 Cow's milk ≥15 ≥5 if age <1 y ≥8 ≤2 Peanut ≥14 ≥8 ≤2 = history of prior reaction ≤5 = no history of prior reaction ≤3 Fish ≥20 Choose testing wisely – not at random for multiple things

Double-Blind, Placebo-Controlled Food Challenge Considered the “gold standard “ for diagnosing food allergies Selection of foods is based on history and/or diagnostic tests A positive skin test to a food to which a patient reported an anaphylactic reaction may be considered diagnostic and DBPCFC unecessary Oral food challenges have potential of decreasing anxiety for kids and families r/t anaphylaxis – giving kids more normal lives – also has postiive nutritional implications – particularly milk –adding needed calcium and vit d to diet OFC – ALWAYS IN OFFICE

IgE Mediated Reactions: Oral Challenge Testing Oral food challenge is the gold standard for diagnosis DBPC is ideal, but not often done outside of academic/research setting Open food challenge is most common Start with very small dose and slowly increase to normal serving size Must have emergency medicine available Results can be confounded by subjective reactions Reevaluation of children with food allergies is warranted to determine if still with allergy – periodic every 1-2 years

The Oral Allergy Syndrome Symptoms are associated with the ingestion of fresh fruits and vegetables Symptoms generally have a rapid onset and resolution Characteristic symptoms include pruritus of the lips, palate, tongue and throat. Confined to the oropharynx

The Oral Allergy Syndrome Symptoms of throat closing are a potential systemic and life-threatening reaction and should not be confused with symptoms of oral allergy syndrome, which is a self-limiting condition Oral allergy syndrome is frequently seen in patients with seasonal allergic rhinitis due to cross-reactivity between some pollens and foods. Oral allergy syndrome or OAS is a type of food allergy classified by a cluster of allergic reactions in the mouth in response to eating certain (usually fresh) fruits, nuts, and vegetables that typically develops in adult hay fever sufferers.[1] OAS is perhaps the most common food-related allergy in adults. OAS is not a separate food allergy, but rather represents cross-reactivity between distant remnants of tree or weed pollen still found in certain fruits and vegetables. Therefore, OAS is typically only seen in tree and weed allergic patients, and is usually limited to ingestion of only uncooked fruits or vegetables.[2] Another term used for this syndrome is '"Pollen-Food Allergy."' In adults up to 60% of all food allergic reactions are due to cross-reactions between foods and inhalative allergens.[3] OAS is a Type 1 or IgE-mediated immune response, which is sometimes called a "true allergy". The body's immune system produces IgE antibodies against pollen; in OAS, these antibodies also bind to (or cross-react with) other structurally similar proteins found in botanically related plants. OAS can occur anytime of the year but is most prevalent during the pollen season. Individuals with OAS usually develop symptoms within a few minutes after eating the food.[4]

Pollens and cross reactive foods in patients with OAS Pollen/plant Fruit/vegetable Birch Apple, cherry, apricot, carrot, potato, kiwi, hazelnut, celery, pear, peanut, soybean Ragweed Melon (eg, cantaloupe or honeydew), banana Grass Kiwi, tomato, watermelon, potato Mugwort Celery, fennel, carrot, parsley Latex Banana, avocado, chestnut, kiwi, fig, apple, cherry

Food is the leading cause of anaphylaxis in children

Anaphylaxis in Food Allergy: Definition Criterion 1 — Acute onset of an illness (over minutes to several hours) involving the skin, mucosal tissue, or both AND AT LEAST ONE OF THE FOLLOWING: Respiratory compromise (eg.,dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg.,hypotonia, syncope, incontinence). Criterion 2 — TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure TO A LIKELY ALLERGEN FOR THAT PATIENT (minutes to several hours): Involvement of the skin-mucosal tissue Respiratory compromise Reduced BP or associated symptoms Persistent gastrointestinal symptoms Criterion 3 — Reduced BP after exposure TO A KNOWN ALLERGEN FOR THAT PATIENT (minutes to several hours).

Anaphylaxis in Food Allergy: Epidemiology Food allergy is estimated to cause 50% of anaphylaxis cases treated in EDs One survey estimated 30,000 ED visits per year due to food-induced anaphylaxis Peanuts, tree nuts and seafood are responsible for most cases in adults Milk and egg cause most cases in children Estimated 150 deaths per year from food allergy in U.S.

Non-IgE-mediated Food Hypersensitivity

IgE vs. IgG testing IgG antibodies are found in both allergic and non-allergic people. Experts believe that the production of IgG antibodies is a normal response to eating food and that this test is not helpful in diagnosing a food allergy. At present, there are no reliable and validated clinical tests for the diagnosis of food intolerance. While intolerances are non-immune by definition, IgG testing is actively promoted for diagnosis, and to guide management. These tests lack both a sound scientific rationale and evidence of effectiveness. The lack of correlation between results and actual symptoms, and the risks resulting from unnecessary food avoidance, escalate the potential for harm from this test. Further, there is no published clinical evidence to support the use of IgG tests to determine the need for vitamins or supplements. In light of the lack of clinical relevance, and the potential for harm resulting from their use, allergy and immunology organizations worldwide advise against the use of IgG testing for food intolerance.

Food induced enterocolitis Generally presents in infants between 1 week and 3 months of age Major symptoms are protracted vomiting and/or diarrhea Cow milk, soy protein or both are most often responsible Symptoms usually resolve after 72hours of allergen avoidance Whey based formula as a place to start for babies with family hx of allergies – Formulas to start with are hydrolyzed casein based formulas then to amino acid based formulas

Food-induced proctocolitis Presents during first few months of life Hematochezia is (gross or occult) is a distinguishing feature Cow milk or soy protein are usually implicated May co-exist with Clostridium Difficile infection The c-diff is after 8 weeks – guiac positive mucousy stools +/- vomiting

Food-induced Enteropathy Malabsorption syndrome Presents in first several months of life Cow’s milk sensitivity is most frequent cause Symptoms : Protracted and/or greasy diarrhea Vomiting Failure to thrive Intestinal lesions may require 6 to 18 months allergen avoidance for complete resolution

The conundrum of formulas Milk based Soy based Hypoallergenic formulas Amino acid based formulas The nursing mom

Allergic Eosinophilic Gastroenteritis/Esophagitis Intolerance to multiple foods, IgE or non-IgE mediated mechanisms Eosinophils infiltrate esophageal, gastric or intestinal walls Symptoms include nausea/ vomiting, abdominal pain, diarrhea, GERD, early satiety or food refusal, dysphagia, weight loss, growth failure Symptoms subside within 3-6 weeks of allergen elimination - this is diagnosed endoscopically – have greater than 20 eos per hpf – treatments of allergic disease are 1-2 things – eoe – pulmicort vs diet vs amino acid diet Gastritis – use mast cell stabilizers – gastrocrom

Elimination Diets Therapeutic trials Used only for a limited period of time (10-14 days) Monitor outcomes closely Adequate education before starting is key to avoiding failure

Elimination Diets Basic Elimination Diet (6 food) Milk, soy, egg, wheat, tree nut, peanut, fish/shellfish Targeted Elimination Diet Severe Elimination Diet

Celiac Disease Gluten-sensitive celiac disease produces a more extensive enteropathy, leading to malabsorption Sensitivity is to gliadin, the alcohol-soluble portion of gluten Found in wheat, oat, rye and barley Treatment requires lifelong elimination of gluten This is an iga mediated response – not an allergy – it is not an allergy to wheat -

Food Intolerance Accounts for the majority of adverse food reactions Not an immunologically mediated response May include: Abnormal metabolic responses (ie lactase deficiency) Unusual susceptibility to pharmacologic substances in certain foods (ie caffeine, tyramine)

Fig E1 Journal of Allergy and Clinical Immunology 2014 134, 1016-1025.e43DOI: (10.1016/j.jaci.2014.05.013) Copyright © 2014 Terms and Conditions

Managing the Patient with Food Allergy Nonpharmacologic Management: Strict avoidance of the offending food allergens is the only proven therapy Symptomatic reactivity to food allergens is often lost over time except for: Peanuts Fish Tree nuts Shellfish Ensure families understand what needs to be removed and that unnecessary food removal do not occur – ie if allergic to wheat – ensure not all grains removed –just cause Extensive eliminiation diets are not warranted This is different in tree and peanut situations – more targeted testing may need to be conducted same with shellfish – In milk – goats and sheep milk should also be avoided as are casein based

Managing the Patient with Food Allergy Pharmacologic Management Epinephrine is the treatment of choice for severe reactions to food Doses may be repeated every 15 minutes for up to 3 doses Delayed, biphasic or prolonged anaphylaxis occurs in more than 20% of cases and so extended observation is required in all cases Prophylactic management has not been proven safe or effective

Patient Education Allergen identification (i.e., how to read food labels) Avoidance strategies and counseling Symptom recognition Cautions regarding the possibility of a life-threatening reaction What to do in case of accidental ingestion Development of a treatment plan How to self-administer epinephrine New data from the allergy world is stuggesting that regular exposure to heat modified egg and milk protein in allergic patients may be tolerated in up to 70% of patients and may be clinically beneficial – Recent data suggests that it accelerates development of tolerance – an observed food challenge with something like a muffin may be warranted in a controlled environement to ensure safe consumption

Other concerns Nutrition Bullying Social stigma Siblings Food introductions in infants Vit d Consider testing siblings of kids with high allergies – consider testing prior to introduction particularly peanuts, egg and milk – in babies with milk and egg allerries – 69% had sensitization to peanuts – should be done by allergist – Experts recommend that intro of solid foods potentially allergenic foods should not be delayed more than 4-6 months of age – recommendation is based on recent studies that support delayed introduction of allergens such as milk egg wheat and peanuts as possible risk factors for allergy or atopic disease

Food Allergy: Prevention We do not know how to prevent food allergies Diet restriction in pregnancy not recommended Exclusive BF for 6 months is best Diet restriction while BF: in high risk patients, avoid high risk foods (peanuts, tree nuts, milk, egg) If supplementing, extensively or partially hydrolyzed formula is best No evidence that delaying introduction of solid foods has any effect

Food Allergy: Resources for Patients Food Allergy and Anaphylaxis Network www.foodallergy.org American Academy of Allergy, Asthma, and Immunology www.aaaai.org American College of Allergy, Asthma, and Immunology www.acaai.org