Food Allergies

Abbreviations Used

AD: Atopic dermatitis

CD: Celiac disease

DBPCFC: Double-blind, placebo-controlled food challenge

EoE: Eosinophilic esophagitis

EGID: Eosinophilic gastrointestinal disorder

FA: Food allergy

FPIES: Food protein-induced enterocolitis syndrome

GER: Gastroesophageal reflux

NPV: Negative predictive value

PPV: Positive predictive value

RAST: Radioallergosorbent test

What Is Food Allergy (and What Is Not)?

Food allergy (FA) is an adverse reaction to food arising from a specific immune response that occurs reproducibly upon re-exposure. Many patients assume food allergies are limited to IgE-mediated (immediate hypersensitivity) reactions. Although immediate reactions are most common, most frightening, and most publicized, other food allergies are not IgE- mediated or have mixed IgE/non-IgE mechanisms (Table 1). It is important to identify the specific mechanism whenever possible and to avoid using vague terms such as “food sensitivity” and “food intolerance”.

Non-immunologic adverse reactions to food are probably more common than allergic reactions (Table 2). Furthermore, patients with an external locus of control often blame food for conditions that are not attributable to specific foods.

Table 1: Immunologic adverse reactions to food (food allergies)

Table 2: Non-allergic adverse reactions to foods.

Ige-mediated Food Allergies

IgE-mediated reactions are the most common FAs and the ones with which practitioners and patients are most familiar. Immediate hypersensitivity reactions result when mast cell-bound IgE is cross-linked by antigen. Cross-linking rapidly activates the IgE receptor with the release of pre-formed mediators including histamine and tryptase. The onset of IgE-mediated food reactions is almost always within 1-2 hours and usually much faster, even within 20-30 minutes, although reactions might not peak that rapidly.

Most mast cells live at surfaces interfacing the outside world (skin, eyes, respiratory tract, GI tract, and to a lesser extent bladder and uterus). The signs and symptoms of IgE-mediated food allergy reflect mast cell activation at those sites (Table 3). About 90-95% of FA reactions include but are not limited to cutaneous or gastrointestinal signs and symptoms.

Anaphylaxis is the involvement of two or more body systems or hypotension after the ingestion of a known food allergen. Systemic absorption of mediators released locally, cross-linking of IgE bound to circulating basophils, and activation of the kinin system might all contribute to cardiovascular signs including tachycardia, hypotension, and shock.

Table 3: Signs and symptoms of mast cell activation.

Mixed Ige/non-ige-mediated Food Allergies

In some conditions, FA is IgE-mediated and/or non-IgE-mediated. The identification of the IgE mediated component (if present) is as described above. However, identification of foods causing presumably T cell-mediated reactions can be difficult and often depends on the history, diary-keeping, diagnostic suspicion, and a knowledge of the most common (but not only) foods that cause the condition. Recognizing that the best test for ANY adverse reaction to a food is what happens with ingestion, we are often left to make recommendations without any objective measures when we don’t know the mechanism.

A complete review of these disorders is beyond the scope of this article, but how FA contributes to them warrants discussion.

Introduction

Not a day goes by in a busy pediatric office when no food-allergic children or parents concerned about food allergy are seen. Although 10-25% of people believe they or their children have a food allergy, only 5-8% of children and 1-3% of the general population are allergic. The prevalence is highest in infants and toddlers with moderate to severe atopic dermatitis, patients with certain pollen allergies, and some patients allergic to latex.

The aim of this paper is to differentiate what is and is not food allergy by defining the term and distinguishing it from non-allergic reactions by means of identifying common food allergens, classifying mechanisms of food allergy, their presentations, and by discussing the utility and interpretation of testing.

Atopic Dermatitis (AD)

AD is a chronic, relapsing condition characterized by intense pruritus and rash. The onset of AD is usually very early in life with 90% of patients presenting before age 5. At least 30% of infants and toddlers with moderate to severe AD have FA that triggers (not causes) the disease. In some cases, it is the only trigger. Egg, milk, wheat, and soy account for over 90% of cases. Sometimes, the food allergen is ingested via breast milk. When a young child with AD has specific IgE to egg, milk, wheat, or soy, a trial elimination diet is frequently indicated. If elimination does not lead to improvement, the foods are re-introduced as tolerated. Without specific IgE, trial elimination diets can still be useful with the choice of food(s) eliminated based on the history and observation as to whether there is flaring after ingestion. Children with AD triggered by non-IgE mediated food allergies often develop morbilliform rashes on DBPCFC, rather than urticaria/angioedema typical of immediate-type hypersensitivity.

Eosinophilic Esophagitis (EOE)

EoE has variable and age-dependent presentations. In infants and toddlers, it may present as food refusal, irritability with feeding, gastroesophageal reflux (GER), choking/gagging, or failure to thrive. Those same signs and symptoms may occur at other ages, but once patients are able to articulate their complaints they often describe dysphagia, odynophagia, or a sensation of food getting “stuck” (impaction) during swallowing. Bolus foods such as meat and bread are common offenders. However, EoE can have a much milder presentation as GER unresponsive to proton pump inhibitors and H2 antagonists. Patients are often highly atopic, at least as defined as being sensitized to numerous aeroallergens.

Characteristic endoscopic findings in EoE include eosinophilic microabscesses often mistaken for candidal esophagitis, esophageal concentric rings (“trachealization”), and longitudinal furrows. While the history and endoscopy frequently strongly suggest EoE, it is a biopsy diagnosis with =15 eosinophils/HPF on at least one biopsy. Enumeration of eosinophils is essential because eosinophils may be present in biopsies of GER without EoE. Multiple biopsies should be taken to avoid missing the diagnosis. The presence of eosinophils on biopsy does not indicate a specific food allergy.

EoE is sometimes dependent on specific food and multiple foods have been implicated. In addition to evaluation for IgE-mediated food allergies, patch testing for delayed-type hypersensitivity to foods is sometimes useful. As with tests for food-specific IgE, patch testing lacks some sensitivity and specificity and must be interpreted in the context of the clinical history. Testing should be done to the most common food allergens and any specific foods the patient implicates. On a case-by-case basis, more extensive testing to foods should be considered. Trial elimination of foods the patient identifies as consistent triggers and to which there are positive test is indicated.

Eosinophilic Gastrointestinal Disorders (EGIDS)

The EGIDs are conditions with eosinophilic infiltration in other organs of the alimentary tract. The signs and symptoms depend on the organ involved and the layer in which the eosinophils are found. Upper GI involvement results in nausea and vomiting, whereas lower GI involvement causes pain, cramping, bloating, and diarrhea. Mucosal infiltration is associated with diarrhea, muscular is involvement with cramping and serosal involvement with abdominal pain. More than one layer may be affected. EGIDs are more common in adults than in children.

EGIDs can present similarly to food protein-induced enteropathy (see below), so a biopsy is again required for a formal diagnosis. Enumeration of eosinophils on biopsy is essential as eosinophils are commonly present in biopsies of the normal stomach and intestine. The evaluation of food allergy in EGIDs is analogous to that of EoE, although there are no data on the utility of patch testing.

Non-ige-mediated Food Allergies

Non-IgE-mediated food allergies affecting young children (Table 4) can range from mild and benign to life-threatening. Fortunately, the most severe are also the least common. Milk and soy are more the most common triggers. Presumably T-cell mediated, the specific immunologic mechanisms are not known. The onset of symptoms can be delayed several hours after ingestion.

Table 4: Non-IgE mediated food allergies

Food Protein-induced Enterocolitis Syndrome (FPIES)

FPIES can present as a medical emergency with fever, vomiting, bloody diarrhea, leukocytosis with left shift, and hypovolemic shock. It is often initially confused with viral gastroenteritis or sepsis. It presents early in life and is more common in babies drinking formula than those who are exclusively breastfed. Cow’s milk and soy are the most common triggers with the majority reacting to both. Therefore, patients should be fed elemental formulas. Other foods are less commonly implicated. The diagnosis is usually made clinically. Biopsies may reveal eosinophils, lymphocytes, or neutrophils.

Food Protein-Induced Enteropathy

but is less severe and not life-threatening. As compared to FPIES, children with enteropathy tend to be a little older and usually only react to one food. Enteropathy can be confused with GER or lactose intolerance, but without the removal of the offending food, children may fail to thrive.

Allergic Proctocolitis

Allergic proctocolitis is the most common and benign of the non-IgE-mediated food allergies, presenting early in life with bloody stools. Most affected infants are breastfed and sensitive to both milk and soy. In general, affected infants are otherwise healthy and happy. Allergic proctocolitis must be differentiated from anal fissures.

Non-IGE-Mediated Adverse Reactions to Gluten Containing Grains

As with FA in general, the public perception of the frequency of gluten intolerance is greater than reality. Patients often identify gluten as the cause of subjective and vague complaints including fatigue and other constitutional complaints. However, only celiac disease (CD), non-celiac gluten sensitivity, and IgE-mediated grain allergy have been validated by DBPCFC.

CD can present with a wide variety of phenotypes and must be differentiated from non-celiac gluten sensitivity. While they can present in a similar manner and both require gluten avoidance, CD has other long-term health implications. Patients usually demonstrate anti-tissue transglutaminase IgA and have typical biopsies with crypt abscesses. Tests are negative in the absence of a CD. Negative tests when the patient is gluten-free do not rule out the disease. In those instances, screening for HLA DQ2/DQ8 is useful as most patients with CD carry the genotype. However, only about 40% of HLA DQ2/DQ8 positive patients have CD.

Diagnosing IGE Mediated Food Allergies - The History

A double-blind, placebo-controlled food challenge (DBPCFC) is the gold standard for the diagnosis of FA. However, even before the challenge, the most important tool to identify a potential adverse reaction to food is a thorough history. A supportive history dramatically increases the sensitivity and specificity of tests for food-specific IgE. There are several things to ask about every suspected hypersensitivity reaction to food.

First, what happened? Is the reaction consistent with an IgE-mediated adverse reaction? Were the signs and symptoms as one would expect with mast cell activation? If not, is the reaction consistent with another immunologic reaction, as described below?

What food triggered the suspected reaction? Cow’s milk, egg, soy, and wheat account for over 90% of new-onset FA in infants and toddlers. In older children and teenagers, peanuts, tree nuts, shellfish, and finned fish account for over 90% of new-onset FA. The prevalence of seed allergy has increased over the last two decades. Because other foods are far less frequently allergenic, it is reasonable to think about the most common offenders first when taking a history and testing. Diary keeping can be difficult but is essential for identifying less common allergens including herbs and spices.

Two exceptions to this paradigm of most common food allergens are the Food-Pollen and Fruit-Latex Syndromes in which patients have symptoms (often limited to the oropharynx) after ingestion of fruits and vegetables with homologous epitopes to pollen or latex, respectively.

What is the reproducibility of the reaction? That is, does the reaction occur each time a specific food is eaten? After an initial reaction, many parents do not offer the food a second time, so the answer to this question is often unknown.

How long did it take from ingestion to the onset of symptoms? Did symptoms start within the expected time frame for an immediate-type reaction? How much did the patient eat? If the patient had a mild reaction after eating a large amount of food, it is reassuring but does not preclude more serious reactions with smaller ingestions. Historical details regarding the timing to the onset of symptoms, their progression, treatments provided and their effectiveness, and the time to resolution are useful information for the design of food challenges in appropriate patients and for writing school management plans.

Testing for Food-Specific IGE

In vitro and in vivo testing for food-specific IgE is useful to confirm or refute diagnostic suspicion after a detailed history. The true value of the tests comes with understanding their interpretation. A positive test does not indicate an allergy. It merely reflects sensitization, the presence of specific antibodies. IgE-mediated allergy is sensitization and mast cell activation with exposure; that is, there must be symptoms. When a physician orders individual tests for food-specific IgE based on the history (rather than a “panel”), the statistical value (sensitivity, specificity, positive [PPV], and negative predictive values [NPV]) of the tests improves.

Radioallergosorbent tests (RASTs) are rarely used these days. Instead, in vitro tests that use the same immunologic principles but a different solid medium are preferred. The newer tests are more sensitive and specific than RASTs and in some cases, the sensitivity approaches that of skin tests. There are only a few foods for which we know how to interpret ImmunoCAP® results (milk, egg white, peanut, and codfish). For those foods, if the level is low enough or high enough the NPV and PPV are known. However, the interpretation of results in the grey zone between those lower and upper thresholds can be difficult. In addition, some foods can have very highly elevated levels with low PPV (e.g., soy and wheat levels of 35 kU/L have 50% PPV).

The degree of elevation does not indicate the severity of allergy; it indicates a greater likelihood of allergy. Only the clinical reaction itself is diagnostic of severity. In vitro tests are more expensive than skin tests and take longer to get results. Because of the range of levels reported, they can also be harder to interpret. However, they are not influenced by antihistamine use, skin disease, or behavior of patents resistant to testing.

Skin testing for foods is more specific and often easier to interpret than in vitro tests, but some of the same caveats apply. As within vitro tests, a positive test indicates sensitization, not an allergy. The foods to which we test must be driven by history to improve the statistical value of the results. Negative skin tests have a high NPV for IgE mediated reactions, but positive tests without a supportive history have <50% PPV. Extensive testing without a supportive history is inappropriate. A larger positive skin test indicates a greater likelihood of allergy, but not the severity of the allergy.

In contrast to in vitro tests, antihistamines and tricyclic antidepressants must be withheld before testing. Patients with atopic dermatitis and dermographism are more likely to have irrelevant or false positive tests.

Conclusion

FA is real and common. The term is often misunderstood or misapplied resulting in misdiagnoses, unnecessary testing, and dietary restriction. A detailed history, appropriate testing and interpretation, monitoring of food elimination trials and challenges, and their thoughtful analysis make practitioners better food allergists.