INTRODUCTION — The diagnosis of a food allergy requires consideration of the details of an individual's history, knowledge about the epidemiology of different food allergies, and specific test results. When these elements do not clearly confirm or refute an allergy, the clinician, typically an allergy specialist or sometimes a gastroenterologist, may perform a clinician-supervised oral food challenge (OFC) [1-6]. OFCs may also be used to determine if a food allergy has resolved. In addition, they can be undertaken to define other adverse reactions to foods, such as intolerance.
OFCs generally consist of a gradual feeding of the test food under close observation. The test usually results in a definitive conclusion about whether the food was tolerated.
An OFC is preceded by a period of dietary elimination, performed either therapeutically (because the food was already suspected or known to have caused a reaction) or for diagnostic reasons (to determine if elimination of the suspect food resulted in amelioration of symptoms).
This topic review will present the role of diagnostic elimination diets, the selection of patients for OFCs, different types of OFCs, and a general approach to performing an OFC. Other related food allergy topics are covered separately. (See "Diagnostic evaluation of food allergy" and "Management of food allergy: Avoidance" and "History and physical examination in the patient with possible food allergy" and "The natural history of childhood food allergy".)
ELIMINATION DIETS — Elimination diets are performed prior to an oral food challenge. Elimination diets are used diagnostically to determine if symptoms, usually chronic in nature, resolve after the suspected food(s) is removed from the diet. Elimination diets are discussed in greater detail in another review, and avoidance of a food allergen once the allergy is diagnosed is presented separately. (See "Diagnostic evaluation of food allergy" and "Management of food allergy: Avoidance".)
There are three types of elimination diets:
The type of elimination diet chosen depends upon the clinical history and the results of specific IgE tests.
Acute IgE-mediated reactions — A patient may be instructed to avoid several potential causal foods if a reaction suggesting an IgE-mediated disorder (eg, urticaria) occurred suddenly after a meal, but a single causal food allergen could not be identified by testing or history. It is improbable that more than one food in a given meal would cause a reaction.
Chronic illness — Elimination of multiple foods (eg, oligoantigenic or elemental diet) may be indicated for patients with certain chronic inflammatory diseases. For example, atopic dermatitis and eosinophilic gastrointestinal diseases are associated with food allergy that is usually non-IgE mediated or mixed IgE and non-IgE mediated [7-9]. History, testing, and epidemiologic considerations may yield an extensive list of suspect foods. Thus, elimination of multiple foods is typically needed to determine if the disorder is food-responsive.
Adherence to these diets is difficult, so exclusion of a modest number of high risk foods may be considered instead. A provisional diagnosis of food allergy is given if symptoms resolve, as documented by history, symptom diaries, and/or physical examination. However, OFCs are still needed to confirm the causal foods.
INDICATIONS FOR OFC — The oral food challenge serves two roles in managing food allergies: to confirm diagnosis of a specific food allergy, and to determine if an identified allergy persists or has resolved.
Initial diagnosis — There are several settings in which clinician-supervised oral food challenges may be needed for diagnosis of food-allergic disease:
Assessing resolution — In children with known food allergies, OFCs are commonly performed to determine the safety of adding foods back into the diet when it is suspected that the allergy has resolved. Variables to consider when trying to determine if a food allergy has resolved include specific IgE tests, age of the individual, time since the last reaction, and the outcomes after recent accidental exposures, if any. (See "Diagnostic evaluation of food allergy" and "The natural history of childhood food allergy".)
There is generally no clinical reason to perform an OFC if there has been recent severe anaphylaxis to an isolated ingestion, with a positive test for specific IgE antibody to the causal food. In addition, an OFC may not be relevant when the food or food family being eliminated is not important to the allergic individual’s diet and can be simply avoided (eg, a rarely ingested fruit).
DECIDING TO PROCEED TO AN OFC — Medical and patient factors must be considered when determining if it is appropriate to undertake an OFC (table 1). Patient preferences and concerns are important to consider and should be discussed with the patient/family.
Factors to consider before proceeding with a food challenge include:
OFCs may not accurately reflect reactions outside of the challenge setting, because OFCs use a gradual administration of the tested food and the challenge is discontinued if symptoms occur [23]. Thus, OFCs should not be undertaken solely to document severity.
OFCs performed after a period of elimination have resulted in acute and severe reactions, even though the food was previously associated only with chronic symptoms [2,24,25]. This occurs most commonly when there is a positive specific IgE test for the food. This risk must be considered prior to trial diagnostic elimination diets and during OFCs.
TYPES OF FOOD CHALLENGES — There are three general types of OFCs: open, single-blind, and double-blind challenges [1,26-28].
Open OFC — An open OFC involves gradually feeding the tested food in its natural state (eg, peanut butter) to patients who know that they are eating the food being tested. This method is potentially prone to patient and observer bias because of expectations of a reaction, but it is easy to perform since no special preparation is needed. There is little concern about bias if the patient tolerates the ingestion of the food. However, bias must be considered when symptoms develop, especially if they are subjective.
Open challenges are a good option for screening when several foods are under consideration, or there is minimal concern about observer or patient bias. The test can be repeated with blinding and controls if there is a reaction to an open challenge and there is concern that the reaction may have been anxiety-related rather than physiologic. Open feeding is also used to follow a double-blind, placebo-controlled OFC to ensure a meal-sized portion of the food is tolerated in its natural state. (See 'Single-blind OFC' below and 'Double-blind, placebo-controlled OFC' below.)
Single-blind OFC — Single-blind challenges require that the food be masked in taste by adding it to another food, or hidden in opaque capsules. This procedure helps to alleviate some patient bias. However, the single-blind OFC does not remove observer bias.
The single-blind challenge may be performed with a placebo arm or the operator may decide to use initial placebo doses to observe for subjective symptoms prior to proceeding with the challenge.
Double-blind, placebo-controlled OFC — The double-blind, placebo-controlled, oral food challenge (DBPCFC) is considered the gold standard for diagnosing food allergy and is preferred for research purposes [1]. The tested food is hidden in another food or opaque capsules. Bias is reduced because there are at least two feedings and neither patient nor operator knows which challenges contain the food being tested.
The procedure for DBPCFC is more labor intensive than the open or single-blind challenge, but it can still be carried out in an office setting if the required materials and personnel are available. The aid of a third party is needed to prepare the challenges. A coin flip can be used by the third party to randomize the order of administration. It is sometimes difficult to provide a meal-sized portion of a food in its natural state because the food is masked.
The false positive and false negative rate for the DBPCFC, based primarily on studies in children with atopic dermatitis, is 0.7 percent and 3.2 percent, respectively [29,30].
The placebo arm and active arm may be performed in a single day in patients with a history of IgE-mediated reactions. There should be several hours between challenges. The practice of interspersing placebo and active food proteins during a single challenge (ie, random ordering of sequential doses of placebo and suspected allergen) should be discouraged because it may be difficult to differentiate whether a reaction following a placebo dose was due to the placebo or other factor or was a delayed reaction to the suspected allergen.
As noted above, an open feeding of a meal-size portion of the tested food prepared in its usual manner is often performed as a follow-up to any negative DBPCFC [30]. A DBPCFC may need to be repeated using larger doses or different methods of food preparation if such an open feeding induces a reaction. Although DBPCFCs typically include only two separate challenges (a single placebo and only one active feeding component), increasing the number of challenges to both placebo and active allergen helps to diminish the possibility of a reaction due to chance rather than true allergy; however, this approach is very labor intensive [31,32].
PERFORMANCE OF AN OFC — Consensus has not been reached on a uniform international protocol for performing oral food challenges [1,28,33]. The protocol for oral food challenge (eg, dosing, frequency) may need to be varied to match clinical issues (eg, the history of the reaction pattern). In all challenges, the food is given in gradually increasing amounts.
Patient preparation — Informed consent should be obtained from the patient or guardian, and documented prior to beginning the challenge.
Patients should avoid the suspected food(s) for at least two weeks before the OFC for suspected IgE-mediated allergy and several weeks longer for non-IgE-mediated reactions. Patients should not eat or drink for at least two hours prior to challenge.
Antihistamines, beta-agonists, beta-adrenergic blockers (including eye drops), and other medications that may either alter symptoms of a reaction or interfere with its treatment, should be discontinued for at least five half-lives (specific to each medication) prior to challenge. Patients should be instructed to bring their auto-injectable epinephrine to their appointment, so that it is available to them on the trip home after the test in the event of a delayed reaction.
Patients are advised to cancel the OFC if they are experiencing acute allergic symptoms or are otherwise ill at the time of their appointment. Patients with asthma should be symptom-free and be stable on current therapy with no recent exacerbations. Spirometry may be performed to ensure a good baseline. Infrequently, hospitalization may be necessary to treat severe or acute allergic disease and establish a stable baseline prior to challenges.
Children may be more cooperative if they are supplied with videos, games, and other distractions.
Location — Oral food challenges are almost always performed under direct medical supervision either in a clinic or hospital setting. Options for location include clinician offices, outpatient centers designed for procedures, inpatient hospital units, and monitored intensive care units. In unusual circumstances, foods may be gradually added back into the diet at home. This may be undertaken when specific IgE tests are negative, symptoms are mild or chronic, and there is little concern for potential anaphylaxis. (See "The natural history of childhood food allergy".)
Selection of an appropriate setting requires clinician judgment about risks and availability of advanced treatment of anaphylaxis. Oral challenges can elicit severe anaphylactic reactions in any setting. The physician must have appropriate training and be prepared with emergency medications and equipment to promptly treat such a reaction [2,34].
It is best to perform the challenge in a controlled setting (eg, hospital) if the patient is considered high risk (eg, positive test for IgE, previous anaphylactic reaction, history of asthma). It may also be prudent to have intravenous access prior to commencing challenges in patients with higher specific IgE levels [35] or history of more severe reactions. Intravenous access should be strongly considered for all patients with food protein-induced enterocolitis syndrome (FPIES) undergoing a food challenge, since they are at risk for hypotension with reexposure to the food [36]. (See "Food protein-induced proctitis/colitis, enteropathy, and enterocolitis of infancy".)
Safety — The overall level of risk associated with food challenges has been examined. A retrospective series reviewed 584 OFCs performed in children who were estimated to have a ≤50 percent risk of a reaction [16]. Forty-three percent of the challenges were positive. Thirty-nine percent of the reactions were mild, 33 percent moderate, and 28 percent severe. The type and incidence of the different reactions were cutaneous (78 percent), gastrointestinal (43 percent), oral (26 percent), lower respiratory (26 percent), and upper respiratory (25 percent). No patients had cardiovascular symptoms.
In this series, there was no difference among foods in the severity of failed challenges or the type of treatment required to reverse symptoms, despite presumptions about certain foods causing more severe reactions than others (eg, peanut compared to egg or milk). All reactions were reversed with antihistamines without epinephrine, beta agonists, and/or glucocorticoids. Patients were observed for a minimum of four hours after completion of the challenge, and none had a delayed reaction after discharge.
Another series reviewed 150 food challenges performed in 109 patients aged 6 months to 18 years at a university-based pediatric allergy clinic [37]. Challenges were performed to either confirm an allergy or determine if an allergy had resolved. Patients with a history of severe cardiovascular symptoms were excluded from this series. The median IgE level at the time of the challenge was 1.22 kUA/L for milk, 0.96 kUA/L for peanut, and 0.65 kUA/L for egg. There were 40 (27 percent) positive challenges (milk, 4/39; peanut, 12/37; egg, 13/29; other, 11/45). Only three patients were graded as having severe reactions because they had wheezing. All other positive challenges were mild to moderate in severity and included skin, upper respiratory, and gastrointestinal manifestations. Reaction severity did not correlate with specific IgE level. Thirty-five percent of positive challenges were managed with observation only and 57 percent were treated with an antihistamine. No challenges induced cardiovascular symptoms or required treatment with epinephrine.
Among 718 oral food challenges performed at our institution, most with a risk assessment of 50 percent or less, 36 percent were positive [38]. Fifty-seven percent had isolated skin (n = 109) or gastrointestinal (n = 38) manifestations, and only 12 percent had respiratory symptoms. Antihistamines were administered for 93 percent of reactions, and 9 percent of positive challenges were treated with epinephrine. Thus, the clinician performing OFCs must be prepared to treat anaphylaxis.
Food preparation — In blinded challenges, the allergenic food is hidden either in another food or in opaque capsules.
Opaque capsules are easy to use, but pose several potential problems. Some patients, especially young children, are unable to ingest enough capsules or even swallow them at all. In addition, capsules can bypass oral contact, which would normally provide the earliest symptoms/clues of a clinical response. Finally, slow degradation of capsules may result in overlapping doses (ie, administration of a subsequent dose before the previous dose was fully released). This can lead to unintended administration of a higher than needed dose to elicit symptoms and to more severe reactions.
Alternatively, allergenic foods may be mixed into masking foods. Equipment used for food preparation includes paper plates, cups, disposable utensils, mixing bowls, scale, mortar/pestle, blender, and a microwave. Suggestions for masking foods are shown in the table (table 2) [39,40]. The following points should also be considered:
Dosing and timing — No single approach to dosing and timing is universally established for food challenges. Dose amounts and timing between doses should be adjusted to match the patient's history (eg, if days of ingestion are needed to elicit symptoms) or concerns about heightened sensitivity (eg, starting with minimal doses spaced out over longer periods of observation).
For example, a child with a history of atopic dermatitis flaring over days with milk ingestion, who carries positive IgE tests to milk and has been avoiding this protein for a year, may have an acute allergic reaction on the day of challenge or may experience a flare over days of ingestion. A graded oral food challenge under clinician supervision on the first day would evaluate the risk of an acute reaction, and, if tolerated, following the child's symptoms over the following days with milk added to the diet would evaluate for delayed responses.
The general approach is to select a regimen that is unlikely to result in a severe acute reaction by cautiously and gradually increasing the amount ingested (with the target cumulative dose of a meal-sized portion), while also considering time constraints.
For patients with past food reactions that occurred immediately after ingestion, doses are generally administered at 10 to 15 minute intervals over about 90 minutes, followed by a larger, meal-size portion of food a few hours later.
Different dosing regimens are suggested when performing OFC for food protein induced enterocolitis syndrome. (See "Food protein-induced proctitis/colitis, enteropathy, and enterocolitis of infancy".)
Total dose — One approach used for DBPCFCs [1,13,26] is to administer a total of 8 to 10 grams of the dry food or 100 ml of wet/liquid food (double amount for meat/fish, eg, 20 grams). Dry forms of peanut (flour), milk, and egg are often used. The grams used may not match the protein content of ingested foods in their natural form. Powdered forms with a weight of 8 to 10 grams are approximately equivalent to 105 mL skim milk, 1.2 eggs, and 21 mL of peanut butter.
Starting dose — The starting dose should be low enough that it does not trigger a reaction in most patients. In a small series of adult peanut allergic patients undergoing DBPCFCs, 50 mg of peanut was generally the lowest dose that elicited objective reactions [44]. However, one patient had a systemic reaction to a 5 mg dose. This patient and another experienced mild subjective symptoms at only 100 micrograms of peanut.
Starting doses of 100 mg or less are recommended based upon results from a series of 513 positive challenges to six common allergenic foods in children with atopic dermatitis [13]. In this series, starting doses ranged from 100 to 500 mg. Neither prick skin test size or specific IgE antibody concentration was predictive of the dose required to trigger a reaction. Eleven percent of the reactions that occurred on first dose were severe. The following results were reported:
One could argue for starting doses that begin under the thresholds reported to induce reaction, especially in patients who have a history of reacting to trace amounts of a food [45]. However, threshold data are not available for most foods and the thresholds that are published vary logarithmically. Reactions are usually not reported under 0.25 mg of protein for peanut (1 mg of peanut, an amount about the size of the head of a pin), 0.13 mg for egg (similar to the weight and volume of peanut butter), and 0.6 mg for milk (about 0.02 ml) [46].
The European Academy of Allergology and Clinical Immunology proposed starting doses as follows (shown as protein weight or liquid volume): peanut 0.1 mg, milk 0.1 ml, egg 1 mg, cod 5 mg, wheat 100 mg, soy 1 mg, shrimp 5 mg, hazelnut 0.1 mg [47].
Labial food challenge (placing the food on the lower lip for two minutes and observing for local or systemic reactions in the ensuing 30 minutes) [48], has been suggested by some as a starting point before an oral food challenge. However, this has not been extensively studied and we do not recommend this approach.
Dose escalation — The total amount of food to be administered is given in escalating portions. As an example, for a milk challenge with the target dose of 100 mL (1 mL = 1 percent of the total dose), the doses could be: 1 percent, 4 percent, 10 percent, 20 percent, 20 percent, 20 percent, and 25 percent. However, a variety of other challenge regimens have been used, including lower starting doses, variations in the dosing increments, and different time intervals [22,23].
Monitoring — Patients should be examined carefully prior to an OFC to determine their baseline and to confirm that they do not have any current significant allergic signs/symptoms or an illness that would interfere with assessment and/or treatment of a reaction during the challenge. Vital signs are measured and signs and symptoms are recorded at baseline, prior to each dose, and at set intervals after the final dose. Assessments are made for symptoms affecting the skin, cardiovascular system, and gastrointestinal and respiratory tracts (table 3). Scoring systems are useful in the research setting, but are not generally implemented in clinical practice [1].
Children may become suddenly quiet or assume a fetal position prior to exhibiting more objective symptoms. Early indications of a reaction can include subtle signs such as moving the tongue in the mouth to rub an itchy palate, or ear pulling as an indication of pruritus. Oropharyngeal pruritus or pain often precedes objective symptoms [49,50]. Children with atopic dermatitis may display an eczematous flare.
Discontinuing a challenge — Challenges are terminated when a reaction becomes apparent (eg, new objective symptoms or an increase in objective symptoms over baseline). Expert judgment is needed about whether or not to discontinue a challenge if symptoms are not clear. Generally a challenge is discontinued if subjective symptoms are repetitive or prolonged.
Following a negative oral food challenge in which the allergen was administered in a form not normally eaten (eg, peanut flour or powdered egg), it is essential to perform an open challenge with a meal-size portion of the food in the state in which it is normally ingested (eg, peanut butter or boiled egg). This is done to ensure that the processing of the allergenic food for challenge did not alter the allergen and to confirm the negative result.
Medical treatment for a reaction — Medications are given as needed to treat allergic or anaphylactic reactions. Generally, antihistamines are given at the earliest sign of a reaction. Epinephrine and other treatments are given if there is progression of symptoms or any potentially life-threatening symptoms. (See "Anaphylaxis: Rapid recognition and treatment".)
Severe allergic reactions are an uncommon outcome of oral food challenges in children when typical criteria are used in deciding to proceed with a challenge. In one series, anaphylactic reactions requiring treatment with epinephrine occurred in 4 percent of challenges (11 percent of positive challenges) [51]. These severe reactions more commonly occurred in older children and in children challenged to peanut or tree nuts. (See 'Indications for OFC' above and 'Deciding to proceed to an OFC' above and "The natural history of childhood food allergy", section on 'Monitoring the food-allergic child'.)
Full medical therapy (eg, epinephrine, antihistamines, intravenous fluids, oxygen, vasopressors, and H2-blockers), materials for resuscitation (ie, intubation), and personnel who can manage anaphylaxis should be immediately available. Doses for all rescue medications should be calculated in advance of challenges.
Observation following challenge — After a negative oral food challenge, we typically observe a patient for one to two hours. It is possible to have later onset symptoms, and we extend this period if the history suggests delayed reactions or if prior reactions were severe. We inform the patient not to eat more of the test food that day and to report and treat any symptoms. The food is added to the diet the next day if no delayed symptoms are reported.
Following a positive challenge, we observe patients for a minimum of two hours past resolution of mild symptoms that required minimal treatment and at least four hours for more significant reactions.
Post-challenge counseling — Patients who tolerate a challenge require counseling about how to introduce or reintroduce the food. Some patients and parents may continue to be fearful about eating the food, despite a negative challenge [52]. This can result in continued avoidance [53]. As noted above, avoidance or infrequent exposure may result in resensitization to the allergen. It is therefore important to encourage at least weekly or monthly ingestion of the specific food. Patients should be asked at subsequent visits about regular ingestion of the former allergen. A repeat challenge may be required in patients who have continued to avoid the food.
Patients who have had a negative OFC to one allergen may have remaining food allergies. These patients must be cautioned specifically about cross contamination by foods that are commonly associated with the food that they are now able to ingest.
Some patients may wish to continue carrying epinephrine even when there are no remaining food allergies. Patients may be advised to continue to have epinephrine available until it is clear that the food is tolerated as a routine part of the diet [22].
Patients who have failed the OFC can be partly consoled to know that their hard work at avoidance was necessary. Though reactions may vary and strict avoidance is typically advised, knowledge about the dose causing symptoms may provide helpful information to patients and families [54]. Review of food avoidance measures is also helpful. The nutritional impact of food avoidance should be reevaluated.
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