Provocation Tests

A provocation test may be useful to confirm a history of allergy. An example might be a child who developed wheezing and urticaria minutes after eating a rusk that contained, as its main ingredients, wheat and cows' milk protein. To determine which component, if any, caused the reaction, oral challenges with individual components can be conducted.

However, the results of provocation tests cannot prove that improvement in a disease has been caused by food avoidance. For example, a child with atopic eczema is put on a diet avoiding many foods, and the eczema improves. This improvement could be a coincidence, a placebo effect, or due to the diet. Just because the child is shown to react to a single food does not prove that avoidance of that food was the cause of the improvement.

Open and blind challenges Where the subject and the observer knows the identity of the administered material at the time of the challenge, the procedure is said to be an 'open' challenge. In a 'single-blind challenge' the observer but not the patient or family know the identity of the test material. To avoid bias on the part of the observer, a double-blind challenge is required. A 'double blind' challenge involves exposing the subject to a challenge substance, which is either the item under investigation or an indistinguishable inactive (placebo) substance. Neither the subject nor the observer knows the identity of the administered material at the time of the challenge or during the subsequent period of observation.

The purpose of provocation tests The aim of a food challenge is to study the consequences of food or food additive ingestion. Provocation tests are helpful:

1. to confirm a history (parents' observations of alleged food allergy are notoriously unreliable, as are adults' beliefs about their own allergies);

2. to confirm the diagnosis, for example, of cows' milk protein allergy in infancy, where the diagnostic criteria include improvement on elimination diet and relapse on reintroduction;

3. to see if a subject has grown out of a food intolerance; and

4. as a research procedure.

The food challenge should replicate normal food consumption in terms of dose, route, and state of food. It should also be performed in such a way that the history can be verified. Thus, for example, there is no point solely looking for an immediate reaction if the parents report a delayed reaction.

Open food challenges are the simplest approach, but open food challenges run the risk of bias influencing the parents' (or doctors') observations. Often this is unimportant. But in some cases belief in food intolerance may be disproportionate, and where this is suspected there is no substitute for a double-blind placebo-controlled challenge. An open challenge may be an open invitation to the overdiagnosis of food intolerance. For example, in the UK parents widely believe that there is an association between food additives and bad behavior, but in one series, double-blind challenges with tartrazine and benzoic acid were negative in all cases in a study of 24 children with a clear parental description of adverse reaction.

The double-blind placebo-controlled challenge is regarded as the state-of-the-art technique to confirm or refute histories of adverse reactions to foods. The ability to unravel food-related problems is said to be limited only by the imagination of the physician and a clever dietitian. In fact, the technique is subject to a number of potential limitations, not all of which can be overcome.

Effect of dose In some cases of food intolerance, minute quantities of food (e.g., traces of cows' milk protein) are sufficient to provoke florid and immediate symptoms. In other cases, much larger quantities of food are required to provoke a response. Hill et al. demonstrated that whereas 8-10 g of cows' milk powder (corresponding to 60-70 ml of milk) was adequate to provoke an adverse reaction in some patients with cows' milk protein allergy, others (with late onset symptoms and particularly atopic eczema) required up to 10 times this volume of milk daily for more than 48 h before symptoms developed.

Concealing large doses is difficult Standard capsules that contain up to 500 mg of food are suitable for validation of immediate reactions to tiny quantities of food, but concealing much larger quantities of certain foods (especially those with a strong smell, flavor, or color) can be very difficult.

Route of administration Reactions to food occurring within the mouth are likely to be missed if the challenge by-passes the oral route, e.g., administration of foods in a capsule or via a nasogastric tube. In practice, patients whose symptoms are exclusively confined to the mouth are unusual, and where there is a history of purely oral reactions an alternative challenge procedure can be employed. In subjects who are intolerant to sulfites, it is well recognized that the administration of sulfites in capsules or directly into the stomach via a nasogastric tube usually fails to provoke an adverse reaction, whereas the oral administration of solution will succeed in doing so.

Problems with capsules Capsules are unsuitable for use in children who cannot swallow large capsules, and this is a major limitation as most cases of suspected food allergy are in infants and toddlers. Furthermore, it is unsatisfactory to allow patients or parents to break open capsules and mix the contents with food or drink, as the color (e.g., tartrazine) or smell (e.g., fish) will be difficult or impossible to conceal and the challenge will no longer be blind.

Anaphylactic shock danger There is a danger of producing anaphylactic shock, even if it had not occurred on previous exposure to the food. For example, in Goldman's classic study of cows' milk protein intolerance, anaphylactic shock had been noted prior to cows' milk challenge in 5 out of 89 children, but another 3 developed anaphylactic shock as a new symptom after cows' milk challenge. In a study of 80 children with atopic eczema treated with elimination diets, anaphylactic shock occurred in 4 out of 1862 food challenges. The risk appears to be greatest for those who have received elemental diets.

Effect of disease activity A food challenge performed during a quiescent phase of the disease (e.g., urticaria, eczema, or asthma) may fail to provoke an adverse reaction.

Additive effect of triggers Although some patients react repeatedly to challenges with single foods, it is possible (but unproven) that some patients only react adversely when multiple allergens are given together. There certainly are some subjects who only react in the presence of a nonfood trigger, such as exercise or taking aspirin.

Special types of provocation testing Other than giving a suspect food by mouth, and asking the subject to swallow it, there are some alternative approaches, which are outlined below.

Oral mucosal challenge A small portion of food is applied to the mucosa inside the mouth, and one looks for reactions such as swelling of the lips, and tingling or irritation of the mouth or tongue, possibly followed by other more generalized symptoms such as urticaria, asthma, vomiting, abdominal pain, or anaphylactic shock. Patients with food intolerance commonly make use of these oral symptoms, spitting out and avoiding further consumption of a food that provokes the symptom.

Gastric mucosal challenge In this procedure, an allergen is applied directly to the gastric mucosa via an endoscope, and the mucosa is then observed for signs of a reaction. In addition, it is possible to take biopsies of the gastric mucosa to study the histological changes and measure the tissue concentration of mediators of inflammation such as histamine.

Rectal challenges The standard test to confirm a diagnosis of celiac disease is the jejunal biopsy, in which a small portion of jejunal mucosa is obtained with the aid of a special capsule that is swallowed, and which passes into the small intestine. When in the correct location, the capsule is triggered and withdrawn; it contains a portion of intestinal mucosa, which can then be examined under the microscope. Alternatively, gluten can be instilled into the rectum, in order to look for a reaction that would signify celiac disease. This procedure requires multiple biopsies from the rectum, and it is uncertain whether the results are reliable.

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