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A. DRUG PROVOCATION TEST

Definition:

Drug provocation test (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). 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.

Procedures:

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.

Indication:

There were positive DPTs results showing highest positive reactions towards NSAIDs,

acetaminophen and penicillin antibiotics whereas a few on cephalosporin antibiotics and

macrolide antibiotics. 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.

Contraindication:


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A negative provocation test might reduce the meaningless avoidance suspicious drugs in the

future, particularly for the patients whom suspected with having allergies on drugs. However,

patients with mild sensitivity or a long delay between drug hypersensitivity reaction and allergy

evaluation can contribute to false negative DPTs.

Adverse effect:

To prevent anaphylactic and shock, the blood vessel was secured whereas epinephrine and short-

acting steroid was prepared in advanced.

Type/example:

Acetaminophen, NSAID, penicillin, cephalosporin, cotrimosazole, macrolide and lactose are

among those which showed positive test.

B. CONJUNCTIVAL PROVOCATION TEST

Definisi

The Conjunctivital Provocation Test(CPT) is a diagnosed method that has been used for many

years to reproduce the ocular allergic response. They found ocular challenges to be "safe andhelpful" 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 oneconjunctival sac, this challenge will detect non-specific responses. Over the next 15 minutes eye

and nose symptoms are recorded. If there are no clinical symptoms then an allergen-containing


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solution is deposited into the nose. The dose of allergen is increased at 15-minutes interval until

symptoms or signs develop, the strength of solution that first provokes symptoms then giving aclue 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).

C. BRONCHIAL PROVOCATION TESTS (BPT)

A. Definition

BPT is one of the model test to confirm the diagnosis and etiology of the bronchoconstriction

that ussually suffered patients of asthma. Asthma is a chronic inflammatory disease of the

airways characterised by reversible airway obstruction, inflammation, and hyperresponsiveness

of the airway. 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).

B. Type of BPT

Based on the action for human body, BPT is divided into two types :

Direct Bronchial Provocation TestDirect BPT give the direct result because the agonist acts directly on specific receptors on the

bronchial smooth muscle, causing it to contract (broncoconstriction). The stimulus only

response to inhaled agents, it good test for bronchial smooth muscle. For example of the

Direct BPT, histamin and methacholine.

Indirect Bronchial Provocation TestIts known Indirect BPT because give the indirect/slow result. It have special proccess to get

the result. This stimulus not directly acting in specific reseptor. 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 such as, histamin, leukotrines, and prostaglandin. For example pf the


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Indirect BPT, exercise, eucapnic voluntary hyperpnoea, distilled water, hypertonic saline and

mannitol.

C. Procedure

Preparation: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 othermedications recommended.

c. If there is the laryngoscopy , it shouldnt be eaten anything for 2-3 hours before thetest. If not, fasting is not required.

To get the good and accuarte result, there are some methods:a. Breathing hard and fast into the spirometer to get an initial reading before-bronchial

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 maycause 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 abronchial 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 themethacholine inhalation.

e. Repeat this process several times until tests done. It usually takes 1 to 2 hours tocomplete

D. Indication

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

Direct Bronchial Provocation Test


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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.

Indirect Bronchial Provocation Testthe 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.

E. Contraindication

The absolute contraindications for bronchial challenges are severe airflow limitation (FEV1 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 treatment

Direct Bronchial Provocation TestDirect BPT is inappropriate for giving the currently active asthma.

Indirect Bronchial Provocation Test

F. Adverse effect


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

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

the results.

D. NASAL PROVOCATION TEST

1. DefinitionNasal provocation test (NPT) is an in vivo diagnostic method using allergen that similar

to the natural exposure. (Loureiro, 2012) 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. (Dordal, 2011) 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 controlling

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

edema of nasal mucosa with increased resistance of air flow.

2. ProcedureNPT should be performed after a pharmacological washout period, like H1

antihistamines, benzodiazepins, corticosteroids and mastocyte stabilizers. It should beperformed at least 4 weeks after an undercurrent infectious disease and avoidance of

exercise. Room conditions of temperature and humidity should be fulfilled. (Loureiro,

2012) 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. (Dordal, 2011) The

patient should be sitting and hold his or her breath during application to prevent theallergen 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.

3. Indication


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NPT is indicated in the diagnostic confirmation of allergic rhinitis, especially to evaluate

clinical significance of individual allergens in multisensitized patients. (Dordal, 2012)

NPT is also indicated when inappropriate or difficulties exist in the assessment of a

patients medical history and 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. (Loureiro, 2012) 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 ofallergic origin.

4. ContraindicationGeneral 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.

(Airaksinen, 2007)

5. Adverse EffectThe 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.

(Dordal, 2011)

6. ExamplesA 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 dusts are also used and obtained from the


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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. (Airaksinen, 2007)

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.

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