Provocation tests in medicine: what are they, what are they for, how do they take place?

By Cristiano Antonino On Jul 6, 2022

The provocation test (or ‘challenge test’) is a diagnostic test used in medicine that consists of administering a substance (e.g. a drug or an allergen such as pollen) via various routes to confirm or exclude its involvement in an allergic reaction, when skin tests are unavailable or negative

In simple terms, a given substance is administered to the patient and it is observed whether this substance causes an allergic reaction in the patient.

Frequently, if the substance to be tested is a drug, a provocation/tolerance test is performed, in order to rule out any drugs that cause allergy and to test tolerance to an alternative, chemically or functionally similar drug, so that the first drug can be substituted with it.

High risk of adverse reactions

A provocation test is necessarily performed in a ‘protected’ environment where any serious allergic reactions can be immediately treated by doctors.

This is particularly important because – of all allergological investigations – provocation tests are those that – while offering the greatest diagnostic guarantees – have the highest risk of even serious adverse reactions, so they must be performed in controlled environments where personnel are trained to intervene quickly.

For the same reasons, provocation tests are never performed if the patient has already experienced anaphylactic shock or a severe allergic reaction in the past.

For the same reasons, provocation tests are considered a level-three allergy diagnostic investigation, performed only when level-one and level-two tests have returned a doubtful result:

Level 1 allergy tests:

skin prick test skin provocation test;

skin provocation patch test.

Level 2 allergology tests:

serum IGE assay or Prist test;

radioallergoabsorption test or ‘Rast test’.

Third-level allergy tests

oral provocation test;

bronchial provocation test with methacholine;

conjunctival provocation test;

nasal provocation test.

Elimination tests are also associated with these examinations in some cases.

What does the examination consist of?

The examination consists of the direct administration of a substance that can be

a suspected allergen (specific provocation test);
various types of substances (non-specific provocation tests, such as bronchial tests with methacholine or histamine).

Administration can take place in various ways.

If, for example, a food allergy is suspected, the specific allergen (e.g. peanut or egg protein) is administered orally, usually by capsules.

If asthma is suspected, on the other hand, the allergen is administered by inhalation, e.g. by aerosol.

If contact allergy is suspected, the allergen is administered on the skin.

After taking the substance, the patient is kept under observation, checking for signs of allergy.

Symptoms and signs that indicate allergic reaction

Symptoms and signs that typically indicate allergic reaction are:

nausea;
vomiting;
headache;
irritability;
tension;
ponfi;
asthenia (lack of strength);
general malaise;
itching;
urticaria;
angioedema;
abdominal pain;
diarrhoea;
bloating;
dyspnoea (difficulty breathing with a sense of ‘air hunger’ and choking);
tachycardia (increased heart rate);
tachypnoea (increased respiratory rate);
coughing;
rhinorrhoea (runny nose);
headaches;
sneezing;
lacrimation.

In the event of severe allergic reactions that may even endanger the patient’s life (rare), healthcare personnel present during the test are trained to intervene rapidly with cortisone, antihistamine and adrenaline medications.

Oral provocation test (with food, food additives or drugs)

Oral provocation tests can be performed for the diagnosis of allergic reactions to food or drugs.

The allergen is administered to the patient starting with a low dose and increasing amounts of the allergen are then administered at regular time intervals of about 30 minutes.

For maximum reliability, the provocation test should be performed double-blind (the potential allergen must be flanked by a non-allergenic control substance and obviously the patient must not know which of the two administered substances is the allergen and which is a placebo).

The double-blind placebo-controlled food challenge (DBPCFC) is the reference test for the diagnosis of food allergies.

Oral provocation tests can only be performed in a few specialised centres and they also have the limitation that they are often unable to reproduce what happens to the patient in his or her daily life.

An example of the limitation of oral provocation tests is food-dependent and exercise-induced anaphylaxis: patients suffering from this form only present an anaphylactic reaction if the ingestion of the food to which one is allergic is followed by exercise, in which case the test carried out in a doctor’s office would give false negative results (allergic patient who turns out not to be allergic).

In the case of food allergy, provocation tests are often used if elimination diets have produced a complete disappearance or at least a significant improvement in the clinical picture.

Bronchial provocation test

The bronchial provocation test can be

non-specific with histamine or methacholine;
specific with particular allergens;
with exercise as an asthma trigger.

Methacholine is a substance capable of causing bronchial obstruction in asthmatic subjects, while it does not cause obstruction in non-asthmatic subjects.

The methacholine test involves inhaling this substance and performing several forced spirometry tests.

In the bronchial provocation test with exercise as an asthma trigger, the patient is subjected to exercise for a few minutes, such as running or walking uphill, and to several spirometry tests before exertion and 5, 10 and 20 minutes after the end of exertion.

Nasal provocation test

The patient is administered the allergen by inhalation, such as a specific type of pollen via a spray, at which point the patient’s reaction is observed and a rhinomanometer is used to measure the airflow through the nostrils and the resistance offered to the passage of air: reduced airflow and increased resistance indicate positivity to the test.

The conjunctival provocation test

This test is performed by instilling 1 or 2 drops of the allergenic extract into the conjunctival sac of one eye, using the other as a control.

Lyophilised allergenic extracts diluted in albumin solution are generally used, at increasing concentrations, starting with concentrations of 1:10,000 – 1:1000 of the extract per prick test; the two conjunctival sacs are used alternately, with an interval of 20 – 30 minutes between each test.

Clinical evaluation is performed, as with the nasal provocation test, by means of a score (hyperemia, lacrimation, itching reported by the patient). Any positive reaction occurs within 5-10 minutes.

If the reaction is very intense, oedema of the conjunctiva and eyelids may occur, persisting for several hours (up to 24-48), but usually disappears within a few hours.

In the case of intense positivity, the symptoms can be blocked by instilling vasoconstrictors. Conjunctival scraping can also be performed, as well as an examination of the tears.

This makes it possible to document histologically, in more than half of the positive test cases, a late reaction, with extensive participation of inflammatory cells (at first neutral threads, then eosinophils and then lymphocytes).

It is also possible to study the various mediators released during the reaction on the tear fluid.

It has recently been demonstrated that after specific provocation tests, the appearance of adhesion molecules (ICAM-l) on the epithelial cells of the conjunctiva is observed.

By means of a ‘challenge camera’, a digital visualisation of the conjunctiva is possible in order to be able to follow any late reactions over time, especially at the vascular level.

Skin provocation tests

These are the prick test and the patch test. The prick test is used to detect/exclude the allergen responsible for a respiratory allergy or a food allergy, so it is mainly used if the doctor suspects such an allergy.

Typical patients are those who suffer from oculorhinitis or asthma in both seasonal and perennial forms, or those who, following the ingestion of certain foods, manifest symptoms and signs such as itching and papules in the oral cavity, urticaria, angioedema, asthma, oculorhinitis, gastrointestinal symptoms, edema of the glottis, and anaphylactic shock.

Unless otherwise medically indicated, it is advisable to discontinue any anti-allergic therapies about a week before undergoing the test: such therapies may in fact alter the test and lead to a ‘false negative’ result, i.e. the patient appears NOT allergic when in fact he/she is allergic.

The patch test is used to detect/exclude the allergen responsible for an allergy.

The patch test is indicated in the presence of allergic contact dermatitis eczema and/or atopic dermatitis, which (despite being due to an IgE mediated mechanism or ‘type I hypersensitivity reaction’) also has a late phase reaction (around 24 hours) consisting of the accumulation of neutrophils, eosinophils and T helper lymphocytes: Although the most recommended test to diagnose the latter is the prick test, the patch test is also useful, especially in rare cases where the late phase reaction occurs in the absence of an overt immediate hypersensitivity reaction.

Unless otherwise medically indicated, systemic corticosteroid therapies (by os or injection) at medium/high doses and/or for prolonged periods should be discontinued prior to testing, as they may alter the test result.

Antihistamine therapy, on the contrary, does not interfere with the test result and can be maintained.

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