Testing and challenge procedures to evaluate allergic and asthmatic reactions to food additives

INTRODUCTION — Food additives are synthetic or natural substances added to foods for multiple purposes. Despite the great number of additives used in the food and pharmaceutical industry, only a few have been implicated in true allergic (immunoglobulin [Ig]E-mediated) or other (immunologic or nonimmunologic) adverse reactions [1].

This topic review will discuss testing and challenge procedures used in the evaluation of allergic and asthmatic reactions to food additives. Specific food additives that have been implicated in causing allergic and asthmatic reactions are reviewed separately. (See "Allergic and asthmatic reactions to food additives".)

Other topics that discuss adverse reactions to food additives include:

●Occupational asthma and rhinitis in food workers caused by allergens and irritants used in food production and processing (see "Occupational asthma: Definitions, epidemiology, causes, and risk factors" and "Occupational rhinitis").

●Food additives and hyperactivity or behavioral changes in children (see "Attention deficit hyperactivity disorder in children and adolescents: Epidemiology and pathogenesis", section on 'Dietary influences').

●The oncogenic potential of food additives (see "Risk factors for gastric cancer", section on 'Environmental risk factors').

●Systemic contact dermatitis from food additives (eg, paraben, balsam of Peru, or propylene glycol) (see "Common allergens in allergic contact dermatitis")

INDICATIONS FOR ALLERGY EVALUATION — An allergy evaluation is most likely to be helpful in patients who experience the following types of reactions in temporal association with ingestion of food:

●Anaphylaxis

●Urticaria/angioedema (isolated episodes after eating without intervening chronic symptoms)

●Asthma

All patients with anaphylaxis should be referred to an allergy expert with experience and knowledge about testing and challenge procedures, if possible. Patients with urticaria/angioedema or asthmatic reactions in association with eating who find it impractical or impossible to identify or avoid problematic food(s) reliably should also be referred. Of note, patients with chronic spontaneous urticaria, which is defined as the recurrence of urticaria on most days of the week for six weeks or longer, rarely have allergies to foods or food additives, although many patients are concerned about this. We do not routinely recommend that patients with chronic spontaneous urticaria avoid foods containing additives [2]. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Patient education'.)

Common goals of allergy evaluation are:

●Proving or disproving that a food additive is causing a specific acute reaction, particularly in patients with anaphylaxis.

●Excluding reactions to food additives and liberalizing the diet in people who are avoiding multiple foods because of concerns about possible reactions to food additives.

Reactions to multiple food additives — Patients with verified adverse or allergic reactions to food additives generally react to a single additive. The medical literature does not support the concept of generalized "chemical sensitivity." The term "multiple chemical sensitivity" is usually used to describe patients with subjective illness marked by recurrent, nonspecific symptoms attributed to low level exposures to a variety of ingested and inhaled substances. Evaluation of such patients is discussed separately. (See "Idiopathic environmental intolerance (multiple chemical sensitivity)".)

OBJECTIVE TESTING — Objective testing for food additive reactions includes immunoassays for IgE to a food additive (when available) and skin testing with either a food that contains the additive and caused symptoms in the past or with a purified preparation of the additive.

The testing described in this topic is appropriate when there is a history of anaphylaxis, urticaria/angioedema, or bronchospasm following exposure to a commercially prepared or processed food. Prior to testing or challenge, the list of ingredients in the causative foods should be examined to look for common additives. A small number of additives have been convincingly implicated in anaphylaxis. These include annatto, carmine, erythritol, guar gum, psyllium, carrageenan, lupine, pectin, gelatin, and mycoprotein [3]. Anaphylaxis, urticaria/angioedema, and asthmatic reactions to food additives are reviewed in detail separately. (See "Allergic and asthmatic reactions to food additives", section on 'Anaphylaxis'.)

In the evaluation of a patient with possible food additive sensitivity, screening tests with multiple food additives are unlikely to provide useful information. Instead, testing should only be performed if there is a consistent history of symptoms following exposure to a specific additive. Before testing is attempted, the patient and clinician should review the list of foods ingested and the ingredient list for each food.

In vitro testing — IgE immunoassays are commercially available for some food additives, such as annatto, carmine red, guar gum, and others [4,5]. The sensitivity and specificity of these tests are not well-defined. Thus, a negative result does not conclusively exclude allergy, and further evaluation in the form of skin testing or oral challenge is usually required. A positive result is consistent with allergy but may require confirmation with a challenge procedure, depending on the clinical need for unequivocal diagnosis and the safety of performing a challenge in a given patient.

Skin prick testing — Skin prick testing (or epicutaneous testing) may be performed with an additive-containing food or a purified preparation of the additive. Positive and negative controls must always be included. Allergen skin testing techniques are reviewed separately. (See "Overview of skin testing for IgE-mediated allergic disease".)

Because skin testing to food additives is not well-validated, positive tests should be repeated on volunteers to see if the positive result is an irritant reaction. For example, sulfite solutions can cause irritant skin reactions if too concentrated a solution is used for skin testing. If other people also demonstrate positive results, then it is likely an irritant response, and the patient can be challenged with the food to confirm that no allergy is present. If volunteers have negative results, a challenge can be designed to confirm reactivity but at a much lower starting dose than the patient likely ingested prior to the reaction. In cases of anaphylaxis, a suggestive clinical history, a positive skin test, and negative results in volunteers is usually sufficient to make the diagnosis.

●Testing with food containing the additive – In most cases, skin prick testing with the additive-containing food to which the patient is suspected to have reacted is the most logical initial test. If the result is positive and there are several potential allergens in the food, testing with individual components and additives is then indicated.

●Testing with purified additives – Some additives can be obtained in purified form, and a solution can be prepared for skin prick testing. Skin testing with purified additives has been described for several natural substances, such as gelatin, carmine [6-8], annatto [9,10], saffron [11,12], carrageenan [13], erythritol [14], and carob gum [15]. Variable concentrations have been used for skin testing in the literature, as summarized in the table (table 1).

Obtaining food additives — Food additives can be obtained from several sources. Aspartame, monosodium glutamate, carrageenan, annatto, and some others are available at grocery stores. Dietary grade sulfites are available for homebrewing and winemaking through specialty suppliers. Other food additives can be obtained through hospital pharmacies (eg, butylated hydroxytoluene), life sciences companies (eg, Fisher Scientific, Sigma-Aldrich, others), or commercial food service supply companies (through hospital cafeteria/food preparation division). We recommend pharmacies or commercial food services rather than the internet sources for safety purposes.

CHALLENGES — Double-blind, placebo-controlled oral challenge is the most rigorous challenge design for diagnosing adverse food reactions, although it is usually reserved for research protocols [16,17]. Single-blind, placebo-controlled challenge is more practical in an office setting.

Blinding and masking additives — Opaque capsules are very effective for blinding the patient to what is being ingested. Since the majority of patients undergoing food additive challenges are adults, it is rare that patients have difficulty swallowing large or multiple capsules. A drawback of using capsules is that early oral symptoms are bypassed because the additive does not contact the oral mucosa. In addition, some capsules may be more resistant to digestion, resulting in delayed absorption, although this issue can be circumvented by prolonging the dosing intervals to 30 or 60 minutes [17]. However, our experience is that delayed absorption is not clinically apparent, and we use a 30-minute interval between challenge steps in most cases.

Food additives can be masked in other ways when capsules cannot be used. For example, when challenging patients with asthmatic reactions to a liquid containing potassium metabisulfite, we mask the solution with fresh-squeezed lemon juice and sugar because the flavor of lemonade is strong enough to cover any faint taste associated with the metabisulfite solution. Other foods that are useful for masking flavors or odors are discussed separately. (See "Oral food challenges for diagnosis and management of food allergies", section on 'Food preparation'.)

Placebos — Inclusion of a placebo is strongly recommended to exclude false-positive reactions in patients with anxiety or other subjective reactions. Some patients experience unintentional anticipatory reactions (classic conditioning). Typical symptoms of such reactions and counseling of patients who react to the initial or final placebo doses are reviewed separately. (See 'Reactions to placebo' below.)

We include placebos containing sucrose as the first and last steps of a challenge. We tell patients that placebos will be interspersed with doses of the additive as a matter of routine in order to detect reactions that are caused by anticipation or anxiety. We explain that this is the only reliable way to diagnose these reactions because they can seem as real to the patient as a true allergic reaction. It is recommended that the patient not be told specifically how or when the placebos will be used or other details about the actual challenge protocol, as this could readily bias or prime the patient.

Appropriate challenge doses — The challenge doses used in published studies vary [18,19]. As a general rule, the final dose itself of the challenge should exceed the probable exposure from any one meal.

The Food and Agriculture Organization of the United Nations and the World Health Organization jointly sponsor an international scientific expert committee on food additives, the Joint Expert Committee on Food Additives [20]. This body has estimated acceptable daily intakes (ADIs) for food additives in mg per kg of body weight [21], although for a challenge, a one-time larger dose is acceptable. ADIs for commonly used food additives are included in the table of the mixed food additive challenge (table 2). The doses shown can be used as the maximal doses for graded challenges with individual additives.

Safety issues

●Challenges in patients with past anaphylaxis should only be performed by clinicians with the expertise to manage any resultant symptoms and in settings equipped with the necessary medications (particularly epinephrine), equipment, and support staff. (See "Anaphylaxis: Emergency treatment".)

●In some patients with past anaphylaxis, intravenous access should be obtained prior to challenge in case emergency medications or fluids are required. This is indicated in patients believed to be at risk for moderate-to-severe symptoms during the challenge procedure and in those with significant underlying cardiopulmonary disease. However, challenge would rarely be performed in such patients. Instead, a convincing clinical history and a positive skin test result would likely be sufficient for diagnosis.

●Challenges in patients with asthma should only be performed when the patient's symptoms are controlled.

Patient preparation

●Informed consent must be obtained for any challenge procedure. The risks, benefits, and potential limitations of the procedure should be discussed. A general explanation of the basic structure of a challenge should be provided, although the exact number and content of each step in the protocol is best not discussed. (See 'Placebos' above.)

●Patients should be in their usual state of health and not ill with a cold or other illness.

●Patients with asthma should have their symptoms controlled prior to performing a challenge. Cromolyn preparations and inhaled bronchodilators are held on the morning of the challenge, while other asthma medications are continued. It is our practice to perform oral challenge only if the prebronchodilator forced expiratory volume in one second (FEV₁) is ≥70 percent of the patient's best and ≥1.5 liters.

●Antihistamines should be discontinued according to the elimination half-life of the specific drug.

●Patients with past anaphylaxis should not be on any medications that may increase the likelihood of anaphylaxis or interfere with treatment of anaphylaxis, such as angiotensin-converting enzyme inhibitors or beta-blockers, although there may be individual exceptions to this. We discontinue beta-blockers 24 hours before the challenge.

●All other usual medications should be maintained.

Specific types of challenges — One of the more common types of reactions in clinical practice is asthma exacerbated by foods containing high amounts of sulfite compounds. A challenge protocol for such patients is described below. At Scripps Clinic, we have also designed a mixed additive challenge that is useful in excluding food additives as a cause of various reactions.

Sulfite challenges in asthmatic patients — Asthmatic reactions to sulfites were relatively common in the past. However, in the Unites States, the US Food and Drug Administration banned the use of sulfites in foods served fresh (eg, salad bars) in 1985, and few foods contain problematic amounts of sulfite now (table 3). Thus, sulfite challenges are rarely needed now. The pathophysiology of sulfite sensitivity in patients with asthma is not fully understood, and several distinct mechanisms may be involved [22]:

●The overwhelming majority of sensitive asthmatics react via inhalation of sulfur dioxide generated from sulfite solutions in an acidic environment, such as that of the stomach. These patients only react to ingestion challenges with sulfite-containing solutions (generating sulfur dioxide).

●Two reports described three sulfite-sensitive asthmatics with positive skin tests to sulfite, suggesting IgE-mediated pathogenesis [23,24].

●Some asthmatics with severe reactions to sulfites may have low levels of the enzyme sulfite oxidase, which is necessary to oxidize sulfite into inactive sulfate [25].

The latter two types of sulfite-sensitive patients may respond to low amounts of sulfite ingested in capsule form [26]. An example of a published sulfite challenge protocol is shown in the table (table 4) [27]. This protocol involved skin testing, followed by capsule challenge and solution challenge, thus addressing all possible types of reactions. However, we do not use this protocol.

In the author's practice, we would not perform skin testing unless a patient gave a convincing history of anaphylaxis. Uncommonly, we perform challenges, using either capsules for patients with urticaria or anaphylaxis (up to a maximal single dose of 200 mg) or solutions (using a maximal single dose of 100 mg) for patients with asthmatic reactions (table 5) [1,28]. Patients who do not react to the solution challenge can be assumed to tolerate the capsule challenge.

Mixed additive challenge — Mixed additive challenge is designed for patients who report nonanaphylactic reactions to multiple food items. We usually perform this challenge as a tool to reassure patients that they are not reacting to food additives. The table shows the mixed additive challenge doses used at Scripps Clinic (table 2). Positive reactions to this challenge are not expected, since the chemicals in the mixed additive challenge have rarely or never been associated with IgE-mediated reactions. (See "Allergic and asthmatic reactions to food additives".)

Rarely, we encounter patients who have a reliable and convincing history of allergic reactions (eg, isolated urticarial reaction) following ingestion of highly processed foods, but a single ingredient cannot be identified as a possible culprit. In this situation, a mixed additive challenge may be considered, although the doses may be adjusted depending on severity of reaction. In the unlikely circumstance that the patient's reaction is reproduced, the individual culprit can be determined by follow-up, single additive challenges.

The mixed additive challenge used in the author's clinic is not graded. All of the components (ie, 15 capsules) are given at the same time with water. The period of observation following ingestion of the capsules should be based upon the patient's clinical history. We usually allow twice the amount of time that the patient reported elapsed between ingestion and symptoms in the past (ie, if the patient recalls that symptoms began within 30 minutes, we observe for one hour). In our practice, we no longer administer placebo steps for mixed additive challenge, since we have not encountered patients who develop symptoms. Of note, we do not advise administering this challenge to patients who believe themselves to be "chemically-sensitive." The management of idiopathic environmental intolerance (also known as multiple chemical sensitivity) is discussed separately. (See "Idiopathic environmental intolerance (multiple chemical sensitivity)".)

Administering challenges — Before the first dose, baseline vital signs (heart rate, respiratory rate, and blood pressure) should be measured and recorded. Spirometry is monitored if the patient had an asthmatic or anaphylactic reaction in the past. A physical exam should be performed and documented.

Enough time should be allowed after each step in the challenge that both the clinician and patient are comfortable that sufficient time was allowed for symptoms to occur. We usually double the time from ingestion to symptoms (as reported by the patient) and allow this amount of time between doses. As an example, if a patient's reaction historically occurred 15 to 30 minutes after food ingestion, we would allow one hour between challenge steps.

Monitoring — The patient is observed throughout the procedure. Vital signs, a focused physical exam (with particular attention to the skin and respiratory tract), and spirometry (if appropriate) are usually repeated before each subsequent dose and again if any symptoms occur. The patient is observed for the following:

●Abdominal cramps or pain

●Angioedema (eyelids, face, lips, and tongue with dysphagia or odynophagia)

●Cough

●Diarrhea

●Flushing

●Itching of the mouth, throat, eyes, or skin

●Lightheadedness or fainting

●Nasal congestion

●Nausea

●Runny nose

●Sneezing

●Shortness of breath

●Tachycardia

●Urticaria

●Vomiting

●Wheezing

Subjective symptoms — If patients develop purely subjective symptoms during a challenge that cannot be verified by physical exam, then we reassure the patient and wait for the symptoms to subside. Provided no objective symptoms develop, we proceed with the protocol. It is relatively common for patients to report skin tingling, slight itching (without flushing or urticaria), or a sense of dizziness or lightheadedness (without changes in blood pressure). These unintentional anticipatory reactions may represent a conditioned response.

Reactions to placebo — In our clinical experience, it is not unusual for patients to develop subjective symptoms to placebo, particularly to those placebo doses given at the start of challenge. (See 'Subjective symptoms' above.)

If a patient reacts to the initial placebo dose, we explain that he/she reacted to the placebo dose and his/her symptoms were caused by the body's ability to recreate sensations in a suggestive setting. We find that most patients are reassured to learn that they do not have a potentially dangerous allergy. We then complete the remainder of the challenge. We have not seen patients who react to both placebo and active doses.

Treating symptoms during challenge — In cases of a reaction, prompt treatment is administered with antihistamine (oral, intramuscular, or intravenous), bronchodilator (albuterol for bronchospasm), and/or epinephrine (intramuscular) for symptoms of anaphylaxis. It is important to remember that antihistamines and bronchodilators are inadequate substitutes for epinephrine if reactions are severe. (See "Anaphylaxis: Emergency treatment".)

Reasons to abort challenge — The challenge should be aborted if a patient exhibits symptoms consistent with an allergic or asthmatic reaction, regardless of the need for treatment. Asthmatic reactions are usually defined as a 25 percent drop in FEV₁.

Observation after challenge — If the patient reacts to the food additive and the challenge is aborted, the patient should be observed until symptoms have completely resolved and then for at least two more hours.

If the patient does not react to challenge, a period of at least two hours of observation after the final dose is suggested.

MANAGEMENT OF PATIENTS WITH CONFIRMED REACTIONS — Management consists of avoidance of commercially prepared foods that are likely to contain the additive in question. With the clinician's assistance, the patient should learn about the additive and foodstuffs that commonly contain it and become versed in relevant chemical nomenclature and alternative names for that additive. For patients with asthma, good ongoing asthma care is an important aspect of management because patients with asthma are at increased risk for severe food-allergic reactions. (See "Food-induced anaphylaxis", section on 'Risk factors'.)

Patients with anaphylaxis — Any patient who has suffered anaphylaxis should be supplied with an epinephrine autoinjector, accompanied by verbal and written instructions on how and when to self-administer the drug. (See "Prescribing epinephrine for anaphylaxis self-treatment".)

Epinephrine autoinjectors contain metabisulfite. However, the injection of the amount of metabisulfite contained in an epinephrine autoinjector did not trigger any symptoms or change in lung function in a small group of sulfite-sensitive asthmatics (author's unpublished data), and there are no case reports to suggest that autoinjectors are unsafe for sulfite-sensitive patients.

A personalized anaphylaxis action plan is helpful for providing specific instructions to patients about when and how to treat recurrent episodes (Anaphylaxis Emergency Action Plan - English) (Anaphylaxis Emergency Action Plan - Spanish).

SUMMARY AND RECOMMENDATIONS — Of the thousands of food additives in use, only a small number have been implicated in allergic or allergic-like reactions.

●Symptoms for which an allergy evaluation may be helpful include urticaria and/or angioedema, asthmatic reactions, and anaphylaxis. Allergy evaluation is helpful in both proving that a certain additive is causing a reaction and excluding food additives as a cause of reactions. (See 'Indications for allergy evaluation' above.)

●Immunoglobulin E immunoassays are commercially available for some food additives, although the sensitivity and specificity are not well-defined, and skin testing and/or challenge are often necessary. Skin prick testing (or epicutaneous testing) may be performed with an additive-containing food or a purified preparation of the additive. Suggested concentrations for skin prick testing are provided (table 1). (See 'Objective testing' above.)

●Challenges are often needed for definitively proving or disproving a food additive as the cause of a patient's reaction. Single-blind, placebo-controlled challenges are feasible in an office setting, whereas double-blind challenges are usually reserved for research settings. Additives can be concealed in opaque capsules or masked within strongly flavored foods. We always include placebo steps to elicit reactions caused by anticipation or anxiety. (See 'Challenges' above.)

●The dose of a specific additive administered during a challenge is derived empirically. In some cases, there are published reports to guide dosing. For other additives, a dose is selected that is estimated to exceed what would be ingested in a single meal, without greatly exceeding the acceptable daily intake (table 2). (See 'Appropriate challenge doses' above.)

●Challenges in patients with past anaphylaxis should only be performed by clinicians with the expertise to manage any resultant symptoms and in settings equipped with the necessary medications (particularly epinephrine), equipment, and support staff. Challenges in patients with asthma should only be performed when the patient's symptoms are optimized. (See 'Safety issues' above and 'Patient preparation' above.)

●Patients are monitored throughout the challenge, and any symptoms that develop are promptly and appropriately treated. Patients are observed until all symptoms have fully resolved or if the challenge is negative, for a period of at least two hours after the last dose. (See 'Administering challenges' above.)

●Some patients may react to placebo, usually with subjective symptoms. These individuals can greatly benefit from appropriate counseling. Most are reassured to learn that they do not have a potentially dangerous allergy. (See 'Reactions to placebo' above.)

●Any patient who has experienced anaphylaxis should be supplied with an epinephrine autoinjector, as well as written instructions on how and when to self-administer (a personalized anaphylaxis plan) (Anaphylaxis Emergency Action Plan - English) (Anaphylaxis Emergency Action Plan - Spanish). (See 'Management of patients with confirmed reactions' above.)