Drug Provocation Test

Student Project Immune System and DisorderDRUG PROVOCATION TESTIn Immediate Reaction

SGD B4DITA PRADNYANDARI(1002005119)ELLEN K.(1002005148)BIANCA JEANNE(1002005116)NI KETUT HANNY PUSPITA(1002005007)I G AG ARI K NARAYANA(1002005027)B BOSMAN ARIESTA GST PT(1002005053)GST A RISKA PERTIWI(1002005069)KIRANJIT KAUR(1002005210)FAIRUZIAH B B ALKATIRI(1002005185)VANNEETHA ARIVANANTHAN(1002005212)

Faculty Of MedicineUDAYANA UNIVERSITY2011CHAPTER IINTRODUCTION

Adverse drug reactions (ADRs) are regarded as an important public health problem as they may be potentially life threatening. According to WHO, adverse drug reaction is a harmful, unintended reactions to medicines that occur at doses normally used for treatment.1 There are two major subtypes of ADR, type A reactions which are dose dependent and predictable, and type B which are not dose dependent and unpredictable. Drug hypersensitivity regarded to be the B type of ADR. Further, Gell and Coombs divided drug hypersensitivity into four classes, type I (IgE mediated), type II (IgG mediated: cytotoxic mechanism), type III (IgG mediated: immune complex deposition), and type IV (cell mediated) which also can be divided into 4 sub group (a d) based on the cell mediator.2Prevalence and incidence of drug hypersensitivity vary from many studies based on hospitalized patient (hospital based populations). In USA the incidence ranges from 6% until 15%. From French pharmacovigilance study 6,1%, in Germany 3,8 % and Australia 2% 4%. From out patients and general populations, the study shows 1% - 3% and commonly caused by antibiotics. Annually 1500 patient died because of drug anaphylaxis in USA. Drugs are the leading cause of anaphylaxis in UK (88 of 202 fatality case).3The effect of drug hypersensitivity can be immediate (IgE-mediated, allergic reactions: anaphylactic shock, generalized urticaria, angioedema, or bronchospasm) and non-immediate allergic reactions. Non-immediate reactions may occur several days after the drug administration and include urticaria, maculopapular eruptions, fixed drug eruptions, vasculitis, toxic epidermal necrolysis, the Stevens-Jonson syndrome, and drug reaction with eosinophilia and systemic symptoms. But the most life threatening is anaphylaxis shock.4Because of the dangerous effect of drug hypersensitivity, medical practitioner must be aware when prescribing drugs. Patient one with another has different respond to drug. It increases the difficulties for physician to determine which drug is the best and not causing hypersensitivity effect for the patient. Therefore some test need to be performed to get information about the hypersensitivity and the allergen of the patient.On that purpose, drug provocation test can be performed. Drug provocation test (DPT) is the controlled administration of a drug in order to diagnose drug hypersensitivity reactions. DPT can be used as diagnostic test for both immediate and non-immediate reactions.5 DPTs are performed under medical surveillance, whether this drug is an alternative compound, or structurally/pharmacologically related, or the suspected drug itself. DPT is sometimes termed controlled challenge or re-exposure, drug challenge, graded or incremental challenge, test dosing, re-challenge, or testing for tolerance. DPT is recommended by some specialized centers, allergy societies, and text books, whereas other societies advise against performing DPTs, and some review articles and textbooks do not even mention the method.62Drug Provocation Test

The topic DPT is controversial in general. Therefore it is considered important to every medical practitioner to know about DPT. Specific protocols for every single drug or at least group of drugs would be helpful, where indication, contraindication, substance, dosing, grading of the reaction and test as well as scoring criteria are defined. The objective of this student project is to describe the DPT from the principle of the test, mechanism of drug allergy, indication-contraindication, procedure of the test, test interpretation, safety of the tests, risks of severe reactions, and treatment of the reactions observed.7 We focus in DPT for drug with immediate response.

CHAPTER IICONTENT

2.1Immune Mechanism and Drug Induced Immediate Hypersensitivity (IgE mediated/Allergy)Drugs are exogenous molecules recognized by the body as foreign substances. As a result, an immune response is generated in many cases. Drug immunogenicity increases with increasing molecular size and complexity. Macromolecular drugs such as proteins and peptide hormones are strongly antigenic. However, most drug substances are haptens, and their potential for inducing an allergic response depends on their capacity to acquire antigenicity upon covalently binding to macromolecules generally proteins.8 Two phases, sensitization and elicitation, are necessary to induce a drug-specific immune response. IgE-mediated reactions to drugs are usually thought to depend on the prior development of an immune response to a hapten/carrier complex: B cells need to mature into IgE-secreting plasma cells, and T cells help in this process by interacting with B cells (i.e. CD40-CD40L interaction) and by releasing IL-4/IL-13, which are switch factors for IgE synthesis. This sensitization phase is asymptomatic and may have occurred during an earlier drug treatment. Upon renewed contact with the drug, a hapten carrier complex is formed again, which then cross-links preformed drug-specific IgE on mast cells. The drug itself is normally too small to cross-link two adjacent IgE molecules, and needs to bind to proteins to cross-link. IgE-mediated reactions can cause mild to very severe, even lethal, diseases. In sensitized individuals the reaction can start within seconds after contact with the parentally applied drug, and minutes after oral drug uptake. Symptoms reach from simple local itch, local wheal-and-flare reaction upon parenteral drug application, to acute bronchospasm and generalized urticaria and edema, preferentially periorbital, perioral or genital. More severe and complex reactions are called anaphylaxis, whereby in most cases with anaphylaxis some circulatory events with collapse and (transient) unconsciousness are observed together with a generalized redness, itch or urticaria. Most IgE-mediated reactions to drugs are less severe and often only an urticaria, angioedema or a local wheal may develop. However, any IgE-mediated drug allergy can be potentially life-threatening.2Drug Provocation Test4Drug Provocation Test4

2.2Risk and Disadvantages of Drug Provocation TestThere are several limitations to the seemingly straight forward procedure of DPT. Many people do not take only one drug at a time, and certain adverse events are sometimes indicative, but hardly ever specific for a certain substance.6 Risks and disadvantages of drug provocation tests: Potentially dangerous Read out might be difficult (if subjective, unspecific symptoms prevail) Does not clarify the pathogenic mechanism of the reaction Not completely pathognomic reactions False-negative results can occur False-positive results can occur Co-factors, that are essential for the clinical symptoms might be absent Does not indicate mere sensitization which may become positive under certain circumstances6

2.3Indications for Performing Drug Provocation TestCaution and surveillance is mandatory in all cases, before performing any DPT. Severe reactions in the history, patients with a reduced health status or at increased risk during emergency treatment, require a guarded and especially critical evaluation.6 The indications for DPT fall into four according to European Network of Drug Allergy (ENDA) of European Academy of Allergology and Clinical Immunology, partially overlapping groups6,7 :1. To exclude hypersensitivity in non-suggestive history of drug hypersensitivity and in patients with non-specific symptoms, such as vagal symptoms under local anesthesia;2. To provide safe pharmacologically and/or structurally non-related drugs in proven hypersensitivity such as other antibiotics in lactam-allergic patients. This may also be helpful for anxious people who would refuse to take the recommended drug without proof of tolerance;3. To exclude cross-reactivity of related drugs in proven hypersensitivity, for example a cephalosporin in a penicillin-allergic subject or an alternative NSAID in an aspirin-sensitive asthmatic;Drug Provocation Test5

4. To establish a firm diagnosis in suggestive history of drug hypersensitivity with negative, non-conclusive or non-available allergologic tests, for example a maculopapular eruption during aminopenicillin treatment with negative allergological tests.

2.4Contraindications for Performing Drug Provocation TestDPT with a suspected drug should not be performed in pregnant women or in patients at increased risk due to co-morbidity like acute infections or uncontrolled asthma, or underlying cardiac, hepatic, renal, or other diseases, where exposure might provoke a situation which is beyond medical control. However, exceptions can be made if the drug under suspicion is essential for the patient, e.g. neurosyphilis and penicillin therapy. A pregnant woman suspected for local anaesthetic hypersensitivity, scheduled for epidural anaesthesia/analgesia during labour, and with negative intradermal skin tests performed in the delivery room, may undergo a DPT with the local anaesthetic in the delivery room by the anaesthetist before the insertion of the epidural catheter.DPT should never be performed on patients who have experienced fatal adverse reaction such as anaphylaxis reactions and immunocytotoxic reactions, drug induced hypersensitivity reactions (with eosinophilia) / DRESS or autoimmune disease7, vasculitic syndromes, exfoliative dermatitis, erythema multiforme major / Stevens-Johnson syndrome, and toxic epidermal necrolysis.6

Table 1. Drug-induced reactions, where DPT is generally not recommended or contraindicated 6,7Generalized bullous fixed drug eruptions

Acute generalized exanthematous pustulosis (AGEP)*

Toxic epidermal necrolysis (TEN)*

Stevens Johnson syndrome*

Drug hypersensitivity syndromes (with eosinophilia) / DRESS*

Systemic vasculitis

Specific organ manifestations, e.g.6Drug Provocation Test

blood-cytopenia hepatitis nephritis pneumonitis

Severe anaphylaxis

Drug-induced autoimmune disease (systemic lupus erythematosus, pemphigus vulgaris, bullous pemphigoid, etc.)

* patch testing justified under special conditions, but not oral intake.

2.5Preparation and Method of Drug Provocation Test2.5.1Preparation for provocation procedures There are some preparations before perform a DPT:a.Ethical considerations and Consideration for The PatientEthical issue should be noticed, because this test is a trial in human. The risk-benet ratio must be acceptable, the condition being treated must be serious, no alternative testing method is available or the results are inconclusive. The patient must be informed of the consequences of both the use of alternative treatments and the risks involved in DPT. Written informed consent must be done by the patient before receive DPT.6Patient should be washed out from drug that may alter the result of DPT. The duration varies, depend on the drug.

Table 2. Drugs that may alter the result of DPT, therefore should be washed out according to free interval6MedicationRouteFree Interval

Antihistamine (H1 blocker)Oral, Intravenous5 days

AntidepressantsOral, Intravenous5 days

Glucocorticosteroids*

Long TermOral, Intravenous3 weeks

Short Term, High Dose (>50 mg p.e)Oral, Intravenous1 week

Short Term, Low Dose (