CHAPTER I

INTRODUCTION
Allergy is one of the most widespread diseases of the modern world. More than 25% of the
population in industrialized countries suffers from allergies. 1 Every individual has his or her
own immune system; the stronger the immune system, the healthier will be the person.
Allergies, also known as hypersensitive reactions, occur when the immune system overreacts
to substances that do not affect most people. These substances, also known as allergens, could
be pollen, animal dander, chemicals, fungi, dust mites, or foods such as nuts, eggs, shellfish,
fish, and milk. Different people show different symptoms of allergies, which can be mild
(runny nose) to severe (anaphylaxis). Symptoms generally depend upon the part of body
contacted by the allergen, e.g., pollens from the air enter the respiratory tract via the nose and
cause respiratory symptoms such as cough, itchy and runny nose, nasal congestion, sneezing,
and wheezing. Food allergy related symptoms include vomiting, nausea, abdominal pain, and
diarrhea. Skin allergy symptoms are lesions, rashes, blisters, redness and itchiness, and so on.
In this time there are many test in diagnosed allergy, one of them is provocation test.
Provocation test is generally known to be used widely in various kinds of investigations,
namely pathological mechanisms, immunological and therapeutic aspects of allergic disease.
Provocation tests are being applied by the scientists because they mimic the response of
allergic exposure under controlled conditions. Furthermore, these tests can determine the
exact etiology of allergic disease. There are a few types of provocation tests for certain
allergic cases are being discussed in this paper, namely nasal, conjunctiva, oral, bronchial and
parenteral. Oral provocation tests can be divided into two: drug and food. The provocation
tests which were being used in each of the classification have similar principle.

CHAPTER II
CONTENT
2.1 DRUG PROVOCATION TEST
Definition
A technique of controlled administration of a drug in order to diagnose drug hypersensitivity
reactions is called drug provocation test (DPT). DPT is a tool used in a laboratory
examination to confirm the causative drug and identify safely administering alternative drugs
in patients with adverse drug reaction (ADR).2 It is also good to be used in diagnosing drug
hypersensitivity as it is considered safe and reliable. Furthermore, DPT is more familiar when
it is used as a comparison between the causative drugs and clinical characteristics between
detailed history of ADRs and DPT results. DPT is performed under medical surveillance and
uses drugs which are an alternative compound, a structural or pharmacologically related
substance or the suspected drug itself. Since the application of DPT is controversial, general
guidelines are required to conduct a DPT.
Principles of testing for drug hypersensitivity
The principles of testing for drug hypersensitivity include an accurate identification of
responsible agent for future treatments to avoid labeling someone as being allergic without
good reasons. The work-up of suspected drug hypersensitivity includes a thorough clinical
history and physical examination, succeeded by one or more of the following procedure: skin
tests when available and validated, laboratory tests and ultimately provocation tests. DPT
should only be performed if other, less harmful test methods do not result in relevant
conclusions and if the outcome might thus help clarify an otherwise obscure pathologic
condition. DPT should only be considered after balancing the risk-benefit ratio in individual
patient and is performed as controlled administration under medical surveillance. 3 If original
reaction was delayed and/or not dangerous, DPT may be done on an outpatient basis, but
patients with more severe reactions should be hospitalized for DPT.
Indications for DPT
DPT is used to exclude hypersensitivity in non-suggestive history of drug hypersensitivity
and in patients with non-specific symptoms. It is also indicated to provide safe
pharmacologically and/or structurally non-related drugs in proven hypersensitivity. Cross2

reactivity of related drugs in proven hypersensitivity can also be excluded. Indication of DPT
also includes establishment of a firm diagnosis in suggestive history of drug hypersensitivity
with negative, non-conclusive or non-available allergologic tests.
There were positive DPTs results showing highest positive reactions towards NSAIDs,
acetaminophen and penicillin antibiotics whereas a few on cephalosporin antibiotics and
macrolide antibiotics.2 The scientists could be confirmed with the positive DPTs when the
patients shown skin rash, angioedema and pruritus on their physical examinations. Other
clinical symptoms which might have become obvious in positive DPTs are dizziness,
anaphylaxis, dyspnea and abdominal pain
Contraindications for DPT
DPT should not be performed in pregnant women or in patients at increased risk due to comorbidity which might lead to provocation of a situation beyond medical control upon
exposure to suspected drug.3 However this is exempted if the drug under suspicion is
essential for the patient. DPT should never be performed on patients who have had severe,
life-threatening immunocytotoxic reactions, vasculitic syndromes, exfoliative dermatitis,
erythema multiforme major/Stevens-Johnson syndrome, drug induced hypersensitivity
reactions (with eosinophilia)/DRESS and toxic epidermal necrolysis. DPT should also not be
attempted in patients who had generalized bullous reactions which may be hard to
differentiate from Stevens-Johnson syndrome.
Test Methods3
1. Route of administration
The drug should be administered in the same way as it was given when the reaction occurred;
however, oral route is favoured whenever possible as absorption is slower and developing
adverse reactions can be treated earlier.
2. Test agents
Commercial preparations are typically used. In case of drug combinations, as in some over
the counter (OTC) preparations, the single compounds should be tested independently.
3. Dosage of test preparations and time interval

In general, one should start with a low dose, carefully increasing this and stopping as soon as
the first objective symptoms take place. If no symptoms appear, the maximum single dose of
the specific drug must be achieved, and the administration of the defined daily dose is
desirable. DPT may be completed within hours, days, or occasionally, weeks depending on
the drug and the patients response threshold.
4. Procedure
Some scientists prepared skin test before conducting DPT in certain occasions. They
performed the skin test using intravenous antibiotics for the patients whom they suspected to
have symptoms after administration of an oral antibiotic. When proceeding with DPT, they
started with 25% of a usual therapeutic dose, 50% as a second dose and the third dose was
100%. Giving the intervals of 30 to 60 minutes, the after results of the symptoms were
observed. If there was no symptoms avail during this first try, then the test was proceed with
100% of therapeutic dose of drug after the third dose.
Example
Acetaminophen, NSAID, penicillin, cephalosporin, cotrimosazole, macrolide and lactose are
among those which showed positive test.
5. Assessment of test results
If DPT reproduces the original symptoms, it can be termed positive. If the original reaction is
just manifested with subjective symptoms and challenge testing again leads to similar, nonverifiable symptoms, placebo challenge steps must be performed. Repetition of the previous
dosing of the drug under investigation is highly recommended if these placebo steps are
negative.
6. Management of adverse reactions
The type of reaction and its severity determine the treatment of adverse event during
provocation testing. The first measure is to stop further test drug supply, followed by
adequate general and specific procedures according to the treatment of anaphylactic
reactions. Introduction of suppressive or remittive therapy should only be started when the
symptoms are sufficiently specific to allow calling the reaction a conclusive test result.

2.2 CONJUNCTIVAL PROVOCATION TEST

Definition
The Conjunctivital Provocation Test (CPT) is a diagnosed method that has been used for
many years to reproduce the ocular allergic response. 4 They found ocular challenges to be
"safe and helpful" in confirming a diagnosis of allergy when the history and skin tests were
inconclusive. Skin prick and blood tests are most commonly used to identify allergy to
airborne allergens that cause eye symptoms. However, there may be special instances when
an allergy is expected that predominantly affects the eyes, but the standard tests fail to show
it. For example, when it is suspected that asthma is being caused by a substance encountered
at work, and when no commercial extract of that substance is available, then a challenge test
may be the only way of confirming the allergy. In other situations the standard allergy test
may fail to show up an allergy to a substance strongly suspect of causing the symptom
possibly because a different allergic mechanism is operating, or possibly because the
sensitivity is confined only to the eye and therefore does not show up in the skin or blood.
Procedure
Conjunctival provocation begins with administration of a drop of diluent solution into one
conjunctival sac, this challenge will detect non-specific responses. 4 Over the next 15 minutes
eye and nose symptoms are recorded. If there are no clinical symptoms then an allergencontaining solution is deposited into the nose. The dose of allergen is increased at 15minutes interval until symptoms or signs develop, the strength of solution that first provokes
symptoms then giving a clue as to the degree of sensitivity to that substance.
Adverse effect
Side effects were accessed and recorded according to the localization of the Inflammation
local or systemic) and reaction of immune response (immediate or delayed).4

2.3 BRONCHIAL PROVOCATION TESTS (BPT)

Definition
BPT is one of the model tests to confirm the diagnosis and etiology of the
bronchoconstriction that usually suffered patients of asthma. Asthma is a chronic
inflammatory disease of the airways characterized by reversible airway obstruction,
inflammation, and hyperresponsiveness of the airway.5 The etiology of asthma ussually from
specific allergen, BPT also can lead to understand the specific allergen that make the asthma
relapse. The physiological hallmark of asthma is Bronchial hyporesponsiveness (BHR). The
presence and severity of BHR can measured by laboratorium test or Bronchial Provocation
Test (BPT).6
Type of BPT
Based on the action for human body, BPT is divided into two types :

Direct Bronchial Provocation Test

Direct BPT give the direct result because the agonist acts directly on specific receptors on
the bronchial smooth muscle, causing it to contract (bronchoconstriction). The stimulus
only response to the inhaled agents, it is a good test for bronchial smooth muscle. For
example of the Direct BPT are histamine and methacholine.5,6

Indirect Bronchial Provocation Test

Its known Indirect BPT because give the indirect/slow result. It has special process to get
the result. This stimulus is not directly acting in specific receptor. It attach to the all of the
cells, further osmotic stimuli have no direct contractile effect on bronchial smooth muscle;
rather, they cause inflammatory cells to release mediators that cause smooth muscle
contraction. The mediators of the cells are such as, histamines, leukotriene, and
prostaglandin. For example of the Indirect BPT are exercise, eucapnic voluntary
hyperpnoea, distilled water, hypertonic saline and mannitol.5,6

Procedure

Preparation:6
a. Stop taking certain inhaled medications that would be recommended. Stop taking
certain medications for up to 7 days before your test, while you can continue to
use the other medications until some hours before the test. Examples of these

medications include Stiriva, Advair, Serevent, Atrovent, Zyflo, Singulair, Ventolin

and Tornalate.
b. Continue to take other medications but it must be stopped if there are the other
medications recommended.
c. If there is the laryngoscopy , it shouldnt be eaten anything for 2-3 hours before

the test. If not, fasting is not required.

To get the good and accurate result, there are some methods:6
a. Breathing hard and fast into the spirometer to get an initial reading beforebronchial provocation tests. This will help the doctor to evaluate whether the test
causes changes in your airways.
b. spray inhaled nebulized methacholine were given. If there are other agents that
may cause your asthma, test technicians will give them to breathe in as well.
c. Ask the technician any questions you have during testing. You need to take a
bronchial provocation test completely in order to get accurate results. If you are
not sure how to breathe into a spirometer or how inhaling allergens, let him know.
d. Take another test had spirometry lung function is measured again after the
methacholine inhalation.
e. Repeat this process several times until tests done. It usually takes 1 to 2 hours to
complete

Indication
BPT is classified in to two types, so the indication also for each of BPT,6

Direct Bronchial Provocation Test6

People who the allergic asthma when patients do not have symptoms or suspected of
having asthma but do not know the cause of allergens causing it to also accept this test for
diagnosis. However, for people entering an occupation where the environment has known
risks for developing asthma, such as in the timber industry or occupations involving
exposure to low molecular weight compounds such as isocyanates, then Direct BPT entry
may indicate a greater propensity for developing the disease. This is done after you take a
small dose of methacholine, a drug that causes the airways to become constriction in
people with asthma. Then spirometer is used to measure lung function and change
records.6

Indirect Bronchial Provocation Test6

the indication for use of an indirect BPT is to identify an individual with currently active
asthma. American Thoracic Guidelines that a diagnosis of EIB

(Excercise Induced

bronchoconstriction) cannot be made with a methacholine test, and that exercise is

indicated when the presence of EIB would impair the ability of a person with a history
suggesting asthma to perform demanding and lifesaving work (eg, military, police,
firefighters). Suggestion the surrogate challenge by other indirect stimuli, such as
hypertonic saline, mannitol or eucapnic voluntary hyperpnoea, could be successfully used
to identify those with EIB.6
Contraindication
The absolute contraindications for bronchial challenges are severe airflow limitation (FEV1 <
50% predicted or < 1.0 l), heart attack or stroke within the last three months, uncontrolled
hypertension, systolic BP > 200 mmHg, or diastolic BP > 100 mmHg, and known aortic
aneurysm. The relative contraindications are moderate airflow limitation (FEV1 < 60%
predicted or < 1.5 l), inability to perform acceptable-quality spirometry, pregnancy, nursing
mothers, current use of cholinesterase inhibitor medication (for myasthenia gravis) and
epilepsy requiring medical treatment5
Adverse effect

After the test, if it has methacholine causing your airways to narrow, you will receive
nebulizer treatments to reverse its effects.6

If you do not stop taking the medication as your doctor advise you to, you will not be able
to take the test. Certain drugs interfere with the reading and your doctor will not be able to
use the results.6

2.4 NASAL PROVOCATION TEST

Definition
Nasal provocation test (NPT) is an in vivo diagnostic method using allergen that similar to the
natural exposure.7 Only a few publications did analyzing for NPT, despite the high prevalence
of rhinitis (5%-20%) in general population. In an epidemiological study of more than 4000
patients performed by the Spanish Society of Allergy and Clinical Immunology, 55% of
patients come with rhinitis and 28% for bronchial asthma. 8 Although it is not standardized,
NPT is a helpful method because it has several important indications in the diagnosis of
allergic rhinitis. NPT consists of eliciting an allergic response from the nasal mucosa by
8

controlling exposure to allergen. This response is characterized by itching, sneezing,

rhinorrhea, and edema of nasal mucosa with increased resistance of air flow.
Procedure
NPT should be performed after a pharmacological washout period, like H1 antihistamines,
benzodiazepins, corticosteroids and mastocyte stabilizers. It should be performed at least 4
weeks after an undercurrent infectious disease and avoidance of exercise. Room conditions of
temperature and humidity should be fulfilled.7
There are some forms of application depend on the allergen formulation, application site and
mode of application.8
Application for micronized powder encapsulated with lactose using an inhaler,
particularly with allergens those are insoluble in organic solvents.
Application in solution is the most common form.
o Spraying the allergen on the head of the inferior turbinate 0.1 ml/puff
o Application of small disks absorbed by a preset amount of allergen to the
area of the inferior and middle turbinates.
o Allergen nebulization
o Instillation of the allergen solution on the inferior turbinate by using a
syringe, pipette, or dropper. Use a micropipette and small amount of solution
(0.1 ml)
The allergen can be applied unilaterally or bilaterally. Bilateral applications are considered to
be more physiological, whereas unilateral applications should be used for research studies. In
some cases, the evaluation of nasal response should be bilateral, because the parasympathetic
reflex mechanism of the oppositenasal cavity must be calculated. NPT starts with the
application of an inert substance and the same diluent used to prepare the solutions, eg.
Physiological saline solution with phenol 0.4%, ringer lactate solution. Fifteen minutes later,
the nasal response is assessed.8 The patient should be sitting and hold his or her breath during
application to prevent the allergen enter the larynx and lower respiratory tract. The patient
must be observed for 2 hours and informed that symptoms may appear later. Measures should
be taken to ensure that the patient has treatment for any eventual symptoms.

Indication
NPT is indicated in the diagnostic confirmation of allergic rhinitis, especially to evaluate
clinical significance of individual allergens in multisensitized patients.8 NPT is also indicated
when inappropriate or difficulties exist in the assessment of a patients medical history and
9

the results of skin or serological test. NPT is also important in the evaluation of the patients
sensitivity to the allergen especially the nasal response to allergen dose, in the study of
immediate and delayed responses, and in research on the pathophysiological mechanism of
nasal response to allergens. NPT could be considered as a model of specific provocation test
that is easy and quick to perform, in the demonstration of the immediate and late phase
response of type I hypersensitivity reaction. Nose is an integral part of the upper airway and
anatomically related to several airway structures, such as ears and paranasal sinuses and also
eyes.7 NPT is also used to assess the efficacy and safety profile of drugs used to treat.
Similarly, NPT has been used as a laboratory technique in the follow up and monitoring of
clinical response after the administration of specific immunotherapy in patients with allergic
rhinitis. NPT also indicate in the etiologic study of occupational respiratory disease of
allergic origin.
Contraindication
General contraindications for NPT include absence of seasonal allergy, airway infection, and
nasal traumas 1 month before NPT. Other condition that may not allow NPT to be done are
severe nasal polyposis and sinusitis which were treated with surgery and or antibiotics at
minimum 1 month before NPT time, antihistamines and nasal spray should be left off a week
before the test, and oral steroid doses were 10 mg prednisolone.9
Adverse Effect
The main weakness of NPT are the methodological variability such as mode of application
and method of interpretation, the risk of adverse effect such as to ear, nose, throat, and
bronchi and the absence of any comparison with the natural allergen exposure.8
Examples
A study was conducted to find the results of NPT from three-year period at a clinic to
evaluate the results of NPT with various IgE and non IgE mediated agents causing
occupational rhinitis. The allergens those were used in this study are Aspergillus fumigatus,
Cladosporium cladosporioldes and Acremonium kilience for mould provocations, Acarus
siro, Lepidoglyphus destructor and Tyrophagus putrescentiae for mite species, cow allergen,
water-based mouse allergen, pig allergen, and the horse epithelia extract. Flowers and plants
were tested by crude fresh plant extract, dry pure spices also extracted, flours and pure wood
10

dusts are also used and obtained from the workplaces of the patients. Placebo test agents
were matched to the diluent and allergen, they were: NaCl, PBS, lactose, wood dust and SPT
control agent.9
Those NPT s are well tolerated by the patients and no serious adverse effect have occurred.
Half of the patients were diagnosed as having specific occupational rhinitis. The other half,
did not react in the NPT or reacted also in the placebo test. These patients had symptoms
indicating unspecific nasal hyperreactivity also in the medical history and most of them were
considered to have idiopathic rhinitis or upper airway irritation.
2.5 FOOD PROVOCATION TEST
Definition
Diagnosis of food allergy should be based on the observation of allergic symptoms after
intake of the suspected food. The oral food challenge test (OFC) is the most reliable clinical
procedure for diagnosing food allergy. The OFC is also applied for the diagnosis of tolerance
of food allergy. Definitions and diagnosis of food allergy should be based on the presence of
clinical manifestations after ingestion of the offending food. 10 The general methodology for
the OFC is to administer the suspected food in gradually increasing doses under a medical
setting.11 A single trial with intake of a small amount of the suspected food at home or in the
office may help in the introduction of eliminated foods, but is not defined as an OFC, because
it is not diagnostic of food allergy.
Aims and Indication
The OFC is generally carried out for two purposes: diagnosis of food allergy; or
determination of tolerance to the allergic food. Diagnostic OFC is typically used in three
situations. First, if a patient is suffering from chronic allergic conditions such as atopic
dermatitis or persistent gastrointestinal (GI) symptoms, and elimination of the suspected food
ameliorates the symptoms, an OFC to confirm the recurrence of symptoms is considered to
establish an accurate diagnosis. Second, if a patient is suffering from acute allergic symptoms
after eating multiple foods, and a precise history and or in vitro diagnostic testing indicates
some suspected foods, definitive diagnosis of the offending food may be achieved using the
OFC. Third, and most frequently, is with the introduction of a sensitized food as confirmed
by the presence of specific IgE antibody or positive results from a skin prick test (SPT), for
the first time in life. This scenario is mostly the case in infants with atopic dermatitis, but
patients and their family with known food allergy tend to avoid highly allergenic foods such
11

as peanuts, buckwheat and shrimp, particularly if they have ever shown positive specific IgE
titers.
Diagnosis of the achievement of tolerance (outgrowing the allergy) is another important
indication for the OFC. Most infants with egg, 12 milk,13 wheat14 or soybean allergies tend to
outgrow these allergies during childhood. Information on symptoms following accidental
exposure helps determine an indication for the OFC. If the patient has experienced a severe
reaction recently within 1 year, the OFC is not indicated. Patients with strict avoidance of the
allergic food for more than 1 year may be considered for an OFC. Information about daily
consumption of foods containing small amounts of the suspected component is also helpful to
determine indications and procedures for the OFC. Allergies to peanut,15

tree nuts,16

buckwheat or shrimp, especially in older children or adults, are thought to continue

throughout life. An OFC to those foods may not be indicated unless loss of sensitization is
confirmed by negative results from an SPT or specific IgE test.
Contraindication
OFC is relatively contraindicated in conditions that increase the risk of severe anaphylaxis,
such as a recent convincing anaphylactic reaction to the food or unstable asthma. It would not
be recommended to perform an OFC for a patient with recent anaphylaxis to the trigger food.
The length of time that may warrant reconsideration of performing an OFC may vary
according to circumstances including the age of the patient, additional history, and results of
testing. For example, children are more likely than adults to develop spontaneous tolerance to
a food over a short period. To illustrate, a 7-year-old child with severe anaphylaxis to a food
at the age of 4 years who otherwise fits the criteria of being a good candidate for an OFC may
be offered an OFC. In contrast, an adult patient with the same 3-year interval since the
anaphylaxis to the trigger food may be a poor candidate for an OFC. Then, an OFC may be
deferred if there is a high likelihood of reacting to the food as predicted by the food reaction
history, whether immediate or delayed; levels of serum food-specific IgE antibody; and/or
results of quantitative skin prick testing and the patients age.

Other condition that is

contraindication of OFC may include confounding medical conditions and medications that
may interfere with treatment of allergic reactions, such as cardiovascular disease, pregnancy,
and treatment with b-blockers; and medical conditions that may preclude interpretation of the
OFC, such as uncontrolled eczema and severe allergic rhinitis. In these conditions, OFCs are
not suggested unless extenuating circumstances exist, especially if the OFC can be delayed
until the condition resolves. However, in patients with multiple dietary restrictions, OFCs
12

may be considered, even if the chance of a reaction is relatively high, because of the potential
benefit of expanding the diet. For practical reasons, OFCs in infants and young children who
may not cooperate with the feeding might be deferred until the child is older or until special
arrangements are made to provide a longer time to complete the feeding and to provide an
adequate observation period.
Setting and procedure
All institutes at which OFCs are performed have to be fully equipped for access to emergency
treatment. The site may be in-hospital, but an outpatient office or clinic may also be suitable
for some patients in whom severe reactions are not predicted. A safe, clean and comfortable
environment, hopefully free from contact with other patients with infectious diseases, needs
to be provided for patients to spend a long period. Well trained doctors or nurses should keep
in touch with the patient throughout the procedure, and the contribution of a dietitian helps a
great deal.17
The risks and benefits of OFC should be discussed with the patient and parents, and written
informed consent needs to be obtained in most cases. Before proceeding with the OFC, the
patient needs to be stable in terms of allergic symptoms and free from any acute illness.
Antihistamines should have been discontinued for >72 h and any other medications for the
treatment or prevention of allergic diseases discontinued for an appropriate period based
on the duration of action, except inhaled corticosteroids and topical corticosteroid ointments
applied on small areas of skin lesions.
The starting dose should be 1 g (1 ml) or less of the food. 17 The typical challenge scheme is to
divide the total dose into 3-6 incremental doubling doses, such as 1, 2, 4, 8 and 16 g of boiled
egg white or 1, 5, 10, 25, 50 and 100 ml of milk. A challenge with smaller doses should be
considered for patients deemed to be at risk of severe reaction, such as 0.1 ml for the starting
dose of milk.18 When processed food is used for a blind challenge, equivalent doses of
allergen content should be considered and a standardized cooking method may be applied to
minimize the variation of allergen activity. Doses are generally given every 15-30 min over 12 h. A longer dosing interval might be applied for severe patients or for those who have
experienced a late-onset allergic reaction after intake of the suspected food. If a sign of
suspicious reaction appears, the next dose should be postponed to observe the progress of
symptoms, or the same dose should be repeated to avoid overloading. The patient may stay in
hospital for more than 2 h after the final dose is given or the provoked symptoms disappear.

13

Upon discharge, the patient needs to be instructed to observe the possibility of late-onset
symptoms, even after a negative (passed) challenge.

CHAPTER III
SUMMARY
Provocation test is one of the tests which are used to determine the diagnosis of allergy. This
test can describe a clue of an allergy. As an example, drug provocation test, conjunctival
provocation test, bronchial provocation test, nasal provocation test, and food provocation test.
But this test has contraindication and risk of severe allergy reaction. So, this test must be
planned effectively and intensively under control of specialist.
Drug provocation test is considered the most reliable and safe to be used in any investigation.
That is why it is often used as the gold standard to study the hypersensitivity of a medicine
and compare it with adverse drug reaction. Under controlled guidance from the experienced
medical officers, DPT can be done after both the risks and benefits are considered balanced
and can be performed in an individual patient. If the other test methods failed to show any
relevant conclusion, then DPT can be directly performed to see any changes in the result.

14

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17