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Keywords:

  • allergy;
  • double-blind;
  • food allergy;
  • oral food challenge;
  • placebo-controlled food challenge;
  • specific oral tolerance induction

Abstract

  1. Top of page
  2. Abstract
  3. Pitfalls concerning the outcome of oral food challenges
  4. Oral food challenges and specific oral tolerance induction
  5. Conclusions
  6. References

Although controlled oral food challenges are considered to be the gold-standard in the diagnosis of food related symptoms, especially if performed in a double-blind, placebo-controlled food challenges (DBPCFC) manner, there are still many unanswered questions and newer aspects, which may explain some pitfalls encountered during oral food challenges. For stopping an oral food challenge and declaring a challenge as positive or negative, symptoms should be objective and/or repetitive. The time interval between administering the food and observing the clinical reaction is an ambivalent factor. Possible reasons for false negative assessments include inadvertent drug use during oral challenges, and the fact that a short-term specific oral tolerance induction (SOTI) may be induced as increasing amounts of the offended food are administered during a titrated oral food challenge. Possible reasons for false positive assessments are the difficulty to maintain an appropriate strict diet throughout the oral challenge procedure, and that the elimination diet implemented before the oral food challenge in children with atopic eczema and suspected food related symptoms may itself be responsible for immediate type clinical symptoms, which had not been reported by the parents before. Finally augmentation factors are among the most plausible explanations for the inadequate reproducibility of an oral food challenge. Although a 100% standardization of the challenge procedure does not seem realistic, efforts should be made to improve the methodology used so far. On the contrary, the possible relation of DBPCFC and SOTI may offer potential advantages for future therapeutic approaches of food allergy.

Abbreviations:
DBPCFC

double-blind, placebo-controlled food challenge

FDEIA

food-dependent, exercise-induced anaphylaxis

FDEIU

food-dependent, exercise-induced urticaria

SOTI

specific oral tolerance induction

There are several potential pitfalls in the diagnostic work-up of food allergy, as recently described (1). Although controlled oral food challenges are considered to be the gold-standard in the diagnosis of food related symptoms, especially if performed in a double-blind, placebo-controlled manner (2, 3), there are still many unanswered questions. We consider newer aspects, which may explain some pitfalls encountered during oral food challenges.

Pitfalls concerning the outcome of oral food challenges

  1. Top of page
  2. Abstract
  3. Pitfalls concerning the outcome of oral food challenges
  4. Oral food challenges and specific oral tolerance induction
  5. Conclusions
  6. References

When is an oral food challenge positive?

Usually, the aim of any oral food challenge is a ‘yes or no’ answer, to determine whether the patient should receive a specific elimination diet or not. However, in many cases the observer and responsible physician are tempted to assess an oral food challenge as questionable positive or questionable negative. Therefore, proposals for criteria when to stop oral food challenges and declare a challenge as positive or negative may be meaningful.

A clear and ‘objective’ clinical reaction – especially if the time interval between ingestion and clinical reaction is short – may be easy situation to assess an oral food challenge as positive. This is the case, for example, if generalized urticaria is observed, or in anaphylaxis. However, does ‘objective’ means visible, measurable or even quantifiable clinical symptoms? What about vomiting? Vomiting is a clear and visible sign, but of course it may be of psychological origin, e.g. if the patient has an aversion against the offended food or remembers clinical reactions in the past. This may be the case even if the oral food challenge is performed in a double-blind, placebo-controlled fashion. For these reasons, vomiting once should not lead to stopping an oral food challenge; vomiting should be severe and/or repetitive. A symptom, which is repeated a second or third time, is more likely to be a positive response to a given food.

Another situation is the occurrence of urticaria. While one or two wheals around the mouth may simply reflect contact urticaria, and the food may be tolerated if orally administered, generalized urticaria or wheals away from the location of contact on the skin may be a clear and objective positive reaction (in the absence of chronic urticaria or factitious urticaria).

Certainly, highly subjective symptoms such as palpitations, tongue burning or abdominal discomfort are not sufficient to assess an oral food challenge as positive. The situation is more difficult if itching is reported in the mouth or on the skin without other visible symptoms. Although this may represent the beginning of an allergic reaction, a clearer, more objective reaction should be induced, e.g. by administering a higher dose. There is less room for doubt if two or more organ systems are involved, e.g. skin plus the gastro-intestinal tract or skin plus respiratory system. Respiratory symptoms from the upper or lower airways are always a clear sign and should be taken seriously – even if only the nose is affected.

The time interval between administering the food and observing the clinical reaction is an ambivalent factor. Certainly, the sooner the symptom is observed, the more likely this is to be a ‘true’ reaction. Clinical symptoms more than 48 h after the challenge can only be assessed as direct reactions in special cases. On the contrary, many authors do not look for clinical reactions at all after more than 2 h (late phase), which would not allow the diagnosis of an eczematous exacerbation, for example, as a food-related symptom. As eczematous exacerbation is especially difficult to quantify, a severity scoring system should be used such as the SCORAD index (4–6). It seems realistic to require a difference of at least 10 points for a positive reaction.

If a decision is not possible on the basis of a mild or unclear clinical reaction, but one is afraid of harming the patient if the next higher dose is administered, there are two possibilities: wait for another 15 min, or repeat the same dose again. The latter increases the cumulative dose but may avoid the next highest single dose.

False negative and false positive oral food challenges

Possible reasons for false negative assessments

  • • 
    Inadvertent drug use during oral challenges by physicians (e.g. not withdrawing a potentially interfering drug in good time before the challenge) or by parents (e.g. a mother is unaware of interfering effects and administers an antihistamine without the knowledge of the physician).
  • A hypothesis is that a short-term specific oral tolerance induction (SOTI) may be induced as increasing amounts of the offended food are administered during a titrated oral food challenge, leading to clinical tolerance (see ‘Oral food challenges and specific oral tolerance induction’ section).

Possible reasons for false positive assessments

  • • 
    It may be practically difficult to maintain an appropriate strict diet throughout the oral challenge procedure, e.g. if the staff in a hospital kitchen fail to appreciate the requirements, or simply make a mistake.
  • There are often many other children on the ward and visitors, and they may inadvertently give the child food, which leads to a positive clinical reaction. This may then be attributed to one of other foods in question or to the placebo phase, resulting in a false assessment of the oral challenge as positive.
  • The elimination diet implemented before the oral food challenge in children with atopic eczema and suspected food related symptoms may itself be responsible for immediate type clinical symptoms, which had not been reported by the parents before (7) (see ‘Oral food challenges and specific oral tolerance induction’ section).

Possible reasons for both false negative and false positive assessments Augmentation factors are among the most plausible explanations for the inadequate reproducibility of an oral food challenge. This is true for both false positive and false negative clinical reactions. The best-known augmentation factor is physical exercise. With food-dependent, exercise-induced anaphylaxis (FDEIA) or food-dependent, exercise-induced urticaria (FDEIU) either the food alone or the physical activity alone are well tolerated, while the consumption of the food followed 30 to 45 min later by physical exercise may lead to clear and possibly severe immediate type allergic symptoms (8–11). Other augmentation factors include drugs (e.g. aspirin) (12, 13), alcohol, a warm bath or sauna, hormonal factors (e.g. menstruation), respiratory or gastro-intestinal infections, systemic mastocytosis as an underlying disease, or psychogenic factors (e.g. stress). A combination of these augmentation factors may adversely effect the diagnostic situation or reduce the reproducibility of an oral challenge. In conclusion, if augmentation factors influence a reported reaction, the situation may not be reproducible in double-blind, placebo-controlled food challenges (DBPCFC) where the factors are missing. Conversely, augmentation factors may lead to positive reactions during challenge testing which may not have been present in the past.

Possible consequences of the decision to stop an oral food challenge

  • The time-point when an oral food challenge is terminated may influence the kind of symptoms reported. It may be that immediate type symptoms are seen more often during oral food challenges because authors do not go on to administer sufficiently large amounts of food to elicit eczematous symptoms – even if they are ready to observe late phase reactions.
  • The same may be true for the occurrence of anaphylaxis. Usually, oral food challenges do not involve risking a severe anaphylactic reaction, but are designed to establish the minimum dosage which provides a clear ‘yes or no’ answer as an argument for deciding on a diet. Therefore only minor symptoms are seen and reported, and the danger emanating from the food may be underestimated.

Oral food challenges and specific oral tolerance induction

  1. Top of page
  2. Abstract
  3. Pitfalls concerning the outcome of oral food challenges
  4. Oral food challenges and specific oral tolerance induction
  5. Conclusions
  6. References

Does a prior elimination diet induce immediate type allergic symptoms in an oral food challenge?

In infants with atopic eczema, cow’s milk is often avoided by parents without evidence of clinical relevance. In this case a further elimination diet prior to the oral challenge will not change the situation and the oral food challenge will prove or exclude a clinically relevant allergy without the occurrence of ‘new’ symptoms.

However, an elimination diet before the oral food challenge in children with atopic eczema and suspected food related symptoms might be responsible for immediate type clinical symptoms, which had not been seen by the parents (7). This observation can be explained as a reversed ‘SOTI’ effect. Stopping the daily administration of the food during the elimination phase may lead to the loss of specific oral tolerance with the consequence of ‘new’, immediate type symptoms which the patients had not presented while the food was eaten on a daily basis (Fig. 1A). The immunological background for the phenomenon of previously unobserved immediate type clinical reactions during oral food challenges is not known.

image

Figure 1.  Hypothesis of the relation between titrated double-blind, placebo-controlled food challenges and specific oral tolerance induction. (A) Hypothetical effect of an elimination diet on the pattern of symptoms during an oral food challenge. (B) Hypothetical effect of titration on the outcome of the oral food challenge.

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To underline this hypothesis, it is possible that some people in the general population may be unaware of their food allergy; they are only nonsymptomatic because they are on a daily ‘SOTI’. On the contrary, a considerable number of patients with a history of food allergy do not reintroduce the corresponding food after a negative oral food challenge (14). In future, we recommend taking into account that allergen avoidance may lead to induction of allergic symptoms.

Can titrated oral food challenges lead to specific tolerance induction?

With SOTI in order to achieve tolerance the offending food is administered orally, starting with very low dosages, which are increased slightly every day up to an amount equivalent to the usual daily oral intake (15). Thereafter, the food is given daily in a maintenance dosage. Specific oral tolerance induction seems to be a specific process (tolerance induction with cow’s milk seems not to induce tolerance to hen’s egg), and so far, at least in a subgroup of patients, does not seem to have a long-term effect after termination of regular intake (16).

This is illustrated by a clinical case: A 3-year-old girl (E.Y.) suffered from atopic eczema and the mother suspected food-related worsening. Allergy testing proved sensitization to cow’s milk, hen’s egg, peanut, wheat, and soy. A DBPCFC with cow’s milk, hen’s egg and placebo was started. At the second titration step the child developed nausea and a facial rash (but no vomiting, no urticaria). It was decided to go on with the challenge procedure and the remaining titrated doses (including the repeat full dose the next day) were completely uneventful. Cow’s milk (the responsible allergen after de-blinding) was omitted, but 7 days later the mother fed two teaspoons of yoghurt to the child. Twenty minutes later the girl showed vomiting twice, urticaria in the neck area as well as coughing and wheezing. A cow’s milk free diet was recommended.

A most intriguing hypothesis is therefore that short-term specific oral tolerance may be induced when increasing amounts of the offended food are administered during a titrated oral food challenge (Fig. 1B). This clinical tolerance to the food, however, may be transient. There is evidence that even a few days of avoidance may be sufficient to lose the acquired tolerance (16).

Conclusions

  1. Top of page
  2. Abstract
  3. Pitfalls concerning the outcome of oral food challenges
  4. Oral food challenges and specific oral tolerance induction
  5. Conclusions
  6. References

Double-blind, placebo-controlled food challenges still represent the gold standard for implementing specific diets in food allergic individuals in order to avoid both unjustified diets, which may severely impair growth and development, and also unnecessary consequences if an underlying food allergy is not correctly identified as a cause of the patient’s symptoms. However, several aspects need to be considered to avoid pitfalls. Although a 100% standardization of the challenge procedure does not seem realistic, efforts should be made to improve the methodology used so far. On the contrary, the possible relation of DBPCFC and SOTI may offer potential advantages for future therapeutic approaches of food allergy.

References

  1. Top of page
  2. Abstract
  3. Pitfalls concerning the outcome of oral food challenges
  4. Oral food challenges and specific oral tolerance induction
  5. Conclusions
  6. References