Clinical features of drug hypersensitivity

May be cutaneous, organ-specific, or systemic

Drug allergy
T-cell Maculopapular exanthem (MPE) Bullous exanthem Stevens-Johnson Syndrom (SJS), toxic-epidermal necrolysis (TEN) Acute generalized exanthematous pustulosis (AGEP) Drug induced hypersensitivity syndrome (DiHS), or drug reaction with eosinophilia and systemic symptoms (DRESS) (Interstitial) nephritis, pancreatitis, colitis, pneumonitis, hepatitis Urticaria, angioedema, anaphylaxis, bronchospasm Blood cell dyscrasia, hemolytic anaemia, thrombocytopenia, agranulocytosis Vasculitis Drug induced autoimmunity (SLE, pemphigus ...) IgE

IgG & Compl.

Antibody mediated hypersensitivity reactions (I-III) and delayed type hypersensitivity reactions (IV a-d)
Type I Immune reactant Type II Type III Type IV a IFN, TNF (TH1 cells) Antigen presented by cells or direct T cell stimulation Macrophage activation Type IV b IL-5, IL-4/IL-13 (TH2 cells) Antigen presented by cells or direct T cell stimulation Type IV c Perforin/ GranzymeB (CTL) Cell-associated antigen or direct T cell stimulation Type IV d CXCL-8. GM-CSF, IL-17 (?) (T-cells) Antigen presented by cells or direct T cell stimulation IgE IgG IgG

Antigen

Soluble antigen

Cell- or matrixassociated antigen FcR+ cells (phagocytes, NK cells)

Soluble antigen

Effector Mast-cell activation

FcR+ cells Complement

blood vessel immune complex

Eosinophils

T cells

Neutrophils

platelets Ag

IFN-

TH2 TH1 IL-4 IL-5 eotaxin CXCL8 GM-CSF PMN

CTL

chemokines, cytokines, cytotoxins

cytokines, inflammatory mediators

cytokines, inflammatory mediators

Example of hypersen-sitivity reaction

Allergic rhinitis, asthma, systemic anaphylaxis

Some drug allergies (e.g., penicillin)

Serum sickness, Arthus reaction

Tuberculin reaction, contact dermatitis (with IVc)

Chronic asthma, chronic allergic rhinitis, maculopapular exanthema with eosinophilia

Contact dermatitis, maculopapular and bullous exanthema, hepatitis

AGEP, Behet disease

Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003

Drug allergy: Heterogeneous clinical manifestations & pathophysiology

Urticaria, anaphylaxis Blood cell dyscrasia Vasculitis Maculopapular exanthem Bullous or pustular exanthems (AGEP) Stevens-Johnson Syndrome (SJS), toxic-epidermal necrolysis (TEN) Hepatitis, interstitial nephritis, pneumopathy Drug induced autoimmunity (SLE, pemphigus ...) Drug induced hypersensitivity syndrome (DiHS/DRESS)

Sub-classification of drug allergy

According to Timing of onset Symptoms start <1hr after administration (immediate) vs >1hr (often 6hr) after application (delayed) - Immune mechanism Gell & Coombs classification, type I-IVa-d - Combined Immediate and IgE mediated Delayed and T-cell mediated (rarely IgG) Correlating the clinical manifestations with the immununological mechanisms

Timing of onset
Within 1(-2)* hrs: immediate reactions, mainly IgE mediated; Urticaria, angioedema, bronchospasm, anaphylaxis, and anaphylaxis related symptoms After 1(-2)** hr (often > 6hrs - weeks): delayed reactions, mainly T cell, occasionally IgG mediated: often, but not always skin symptoms
*) the onset of IgE mediated reactions can occasionally occur later, particularly with oral drugs **) the onset of T-cell mediated reactions can occasionally occur early, particularly with previous exposure to the drug

Appearance of symptoms in immediate or delayed type drug allergy

Immediate type: silent sensitization, well tolerated; at re-exposure quick development of symptoms (urticaria, anaphylaxis)
16 14 12 10 8 6 4 2 0

12 9

13 1

13 3

13 5

Delayed type: Sensitization and symptoms often at 8th 10th day of therapy (exanthema)

45 40 35 30 25 20 15 10 5 0

() ()

1 2 3

4 5 6

7 8

9 10 11 12 13 14 15 16 17

13 7

Allergic vs non-allergic drug hypersensitivity

Allergic Immune reactions (T-cells, IgE, IgG against a drug/metabolite with exanthema, urticaria, etc.) Highly specific Dependent of structure Can be dangerous, severe (IgE & T cell reactions!) Cross-reactions to structurally related compounds IgE to drug occasionally detectable (skin tests, IgE-serology)

Non-allergic No immune reaction against the drug detectable, symptoms can occur at the first contact Activation of immunological effector cells (mast-cells, basophil leukocytes, etc) Cross-reactions due to function of drug, not structure Skin tests and serology negative

Drug provocation tests can be positive in allergic and non allergic reactions

Allergic or Non-allergic drug hypersensitivity

Drug-specific IgE with: penicillin/cephalosporin, pyrazolones* quinolones*, (recombinant) proteins
Non-immune hypersensitivty reaction with: NSAID (acetylsalicylic acid, diclofenac*, .) radio contrast media*, muscle relaxants*, gelatine-infusions*
* Both IgE and non-immune mediated mechanisms possible Histamine, LT, TNFa, Tryptase,....
MC

haptencarrier

Clinical symptoms and signs

Type I (IgE mediated) Allergy or non-immune hypersensitivity reaction rapidly appearing urticaria rapidly appearing angioedema, mostly periorbital, oral, genital swellings, with moderate pruritus, in association with generalized urticaria gastrointestinal symptoms: cramps, diarrhoea, vomiting anaphylaxis and anaphylactic shock

Anaphylaxis and anaphylactic shock

Delayed reactions
Due to drug specific T cells T-cells secrete different cytokines The cytokines activate and recruit distinct effector cells Cytotoxic mechanisms are always involved, in some severe reactions (SJS/TEN) even dominating the clinical symptoms Similar mechanism in skin as in internal organs (e.g. interstitial nephritis)

Exanthems
T-cells recognize the drug and exert, depending on their function, a specific pathology

Bullous Exanthem

Maculopapular exanthem (MPE)

Acute generalized exanthematous pustulosis (AGEP)

Acute Generalized Exanthematous Pustulosis (AGEP)

Clinical manifestations Generalized, sterile pustules Fever (>38C) Leukocytosis Aetiology Mainly drugs (~90%) Rapid onset (3-4d) Mercury (~10%) Acute enteroviral infection

Acute Generalized Heterogeneous Exanthematous Pustulosis (AGEP) Patch Tests

Patch tests are frequently positive
The patch test reaction at 48 hrs imitates the early phase of the

disease with T-cell infiltration

After 96 hrs, pustule formation can be observed

Delayed reactions: danger symptoms and signs

Extensive, confluent infiltrated exanthema Bullae, pustules Nikolsky sign Erythrodermia Painful skin Mucosal affection Facial oedema Lymphadenopathy Constitutional symptoms (higher fever, malaise, fatigue): Look carefully if any of these signs is present. Stop all ongoing drugs. Do liver, renal and blood tests.

Serious drug allergies

Both immediate and delayed reactions may be potentially life-threatening Anaphylaxis (immediate reaction) is not the only life-threatening reaction

Mortality in severe, delayed drug hypersensitivity reactions

Mortality

Stevens - Johnson Syndrome (SJS) & toxic epidermal necrolysis (TEN): bullous exanthema and mucosal affection
DRESS (DHiS): Drug reaction with eosinophilia and systemic symptoms (often hepatitis, sometimes pancreatitis, interstitial lung disease, colitis, myocarditis, pleuritis, pericarditis, nephritis ) AGEP (acute generalized exanthematous pustulosis) Isolated hepatitis, interstitial nephritis, interstitial lung disease, pancreatitis

10 30 % 10 %

5% ?

Drugs with potential for serious allergies

Immediate reactions (anaphylaxis) -lactam-antibiotics, pyrazolone, neuromuscular blocking agents, radiocontrast media Delayed reactions (drug-induced hypersensitivity syndromes) Antiepileptics: carbamazepine, lamotrigine, phenobarbital Allopurinol Sulfonamide/Sulfasalazine Nevirapine, Abacavir Certain quinolones Minocyclin, diltiazem

Diagnosis of drug allergy

1. 1. 2. Can it be a drug hypersensitivity ? If so, allergic or nonallergic? Documentation of acute stage: Documentation of the case (semiology, chronology, all drugs taken) Documentation of the severity of symptoms, including laboratory analysis (suspected serious reactions) Establish temporal relationship of drug intake to appearance of symptoms Risk factors (underlying disease) Rule out possible differential diagnosis Identifying the responsible drug

Identifying the responsible drug

1. 2. 3. 4. History Experience with the drug: books indicating specific side effects of drugs Definition of presumed pathomechanism (IgE, T-cell, IgG) Skin tests with non toxic preparations of the drug Skin prick test (SPT); Intradermal test (IDT) Late reading IDT and patch tests Serology/specific IgE Drug specific IgE (available for few drugs only) Basophil activation tests (in theory available for many drugs) Coombs-test in the presence of drug in hemolytic anaemia Lymphocyte transformation/activation test Drug provocation tests (where 4-6 not available/ not validated)
drug imputability and targeted tests Skin and laboratory tests are performed 6 weeks after the acute stage Type of test depending on whether diagnosing immediate or delayed reactions

5.

6. 7.

The responsible drug is identified by a combination of history, clinical experience of

Laboratory tests for serious reactions

Immediate reactions Serum tryptase Serum histamine

Delayed reactions Complete blood count: eosinophilia and lymphocytosis, leukocytosis Liver function tests: ALT, AST, GT, ALP Serum creatinine Urine microscopy and dipstick: nephritis, proteinuria ( CRP )

In late reactions certain laboratory tests are recommended to assess severity

Immediate reactions Serum tryptase

Plasma histamine Serum tryptase 24-hr Urinary histamine metabolite

30

60

90

120

150

180

210 240

270

300

330

An elevated level supports a diagnosis of anaphylaxis. Normal levels do not exclude anaphylaxis.

Immediate reactions Skin prick and intradermal tests

For IgE-mediated reactions Skin prick test (SPT), Intradermal test (IDT) Sensitive & specific Sensitivity 70% if penicilloyl polylysine (PPL), minor determinant mix (MDM), amoxicillin (AX) and ampicillin (AMP) all tested Specificity for most -lactams 97-99% E.g. -lactam penicillins, cephalosporins, anaesthetic agents.

Skin Prick Test (SPT)

Specific Sensitive Simple to perform Rapid (result in 15-20 min) Educational for patient

Intradermal Skin Test (IDT)

More sensitive than skin prick test May induce false positive reactions May induce systemic reactions Should be done only if skin prick test is negative and allergen is highly suspect.

Immediate reactions Drug specific IgE Tests

Commercially available Phadia CAP/ ImmunoCAP (fluorescent enzyme immunoassay, FEIA) Penicilloyl G, penicilloyl V, suxamethonium Less sensitive and more expensive compared to skin testing Sensitivity for penicillins/ amoxycillin from 38-54% Specificity for penicillins/ amoxicillin from 87-100% Results Reported as kU/L Positive 0.7 kU/L (Class 2)

Illustration of a Widely Used Assay (ImmunoCAP System) for Allergen Specific IgE Quantification

Patient IgE

Allergen coupled to ImmunoCAP Conjugate; Enzyme Anti-IgE

Patient IgE ab bound to ImmunoCAP allergen

Fluorogenic substrate

Conjugate bound to patient IgE

Conjugate enzyme reacts with substrate forming a fluorescent product

Immediate reactions Flow CAST

Flow cytometric basophil activation test (FAST, FLOW-CAST or BASOTEST) Based on the flow cytometric evaluation of CD63 on blood basophils, an activation molecule appearing following incubation of blood basophils with drugs or other allergens in vitro -lactams: Sensitivity 50%, specificity 93% when compared with FEIA Greater sensitivity and specificity than FEIA (37.9% and 86.7% respectively) Combination of FAST and FEIA allows identification of 6580% of penicillin allergic individuals. NSAIDs: sensitivity 71-76% Positive Test: > 15% CD63+ (Stimulation Index 2)

Immediate reactions CAST

Cellular Allergen Stimulation test (CAST)-ELISA Sulphidoleukotrienes (LTC4 and its metabolites LTD4 and LTE4) produced upon in vitro stimulation of blood leukocytes (predominantly basophils) by drugs are quantitatively measured -lactams: Sensitivity 46% (range 3580%) Specificity between 79 and 89%.

Delayed reactions Lymphocyte transformation test (LTT)

Measures the proliferation of T cells to a drug in vitro Advantage: Applicable to many different drugs with different immune reactions, as drug-specific T cell are almost always involved in drug hypersensitivity reactions Disadvantages: Test per se is rather cumbersome and technically demanding Sensitivity is limited
Picher WJ, et al. Allergy 2004: 59: 809820

LTT
LTT frequently positive (>50%) Generalized maculopapular exanthema Bullous exanthema Acute generalized exathematous pustulosis (AGEP) DHS/drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS) Anaphylaxis (generalized, severe symptoms) LTT occasionally positive Hepatitis (dependent on type of drug) Nephritis (dependent on type of drug) Urticaria, angioedema Interstitial lung disease* Pancreatitis* LTT rarely positive (<10%) Toxic epidermal necrolysis (TEN) Vasculitis Macular exanthema (without T-cell infiltration) Guillain-Barre syndrome Blood dyscrasia-like idiopathic thrombocytopenic purpura (ITP) Haemolytic anaemia Fixed drug eruption.

Picher WJ, et al. Allergy 2004: 59: 809820

Delayed reactions Patch tests

Drug patch tests are positive in 3250% of patients who have developed a cutaneous drug eruption Advantages Usually positive in AGEP, maculopapular rash, photodermatoses, lichenoid rash, fixed drug eruption Frequently positive for betalactam antibiotics, especially amoxicillin, cotrimoxazole, corticosteroids, heparin derivatives, pristinamycin, carbamazepine, diltiazem, diazepam, hydroxyzine, pseudoephedrine, tetrazepam Disadvantages Low sensitivity (at best 50%) Lack of standardized test reagents.
Barbaud A, et al. Contact Dermatitis, 2001, 45, 321328 Barbaud A. Toxicology 2005; 209:209216

Acute Generalized Exanthematous Pustulosis (AGEP) - Patch Tests

Patch tests are frequently positive
The patch test reaction at 48 hrs imitates the early phase of the

disease with T-cell infiltration

After 96 hrs, pustule formation can be observed.

Courtesy: Pichler WJ

Drug Provocation Tests (DPT)

Indications Exclude hypersensitivity in non-suggestive history or non-specific symptoms ( SBDC,DBPCDC) Provide safe pharmacologically and/or structurally non-related drugs in proven hypersensitivity e.g. beta-lactam antibiotics Exclude cross-reactivity of related drugs in proven hypersensitivity e.g. cephalosporin in a penicillin allergic Definitive diagnosis in suggestive history with negative, non-conclusive or non-available allergological tests

Contraindications Pregnant women Co-morbidity where DPT may provoke situation beyond medical control e.g. Acute infection Uncontrolled asthma Underlying cardiac, hepatic, renal disease Immunobullous drug eruptions Severe systemic initial reaction.

Drug Provocation Tests (DPT)

Risks/benefits explained to patient Informed consent Cessation of antihistamine short-acting (chlorpheniramine, hydroxyzine) 3 days long-acting (cetirizine, loratidine, fexofenadine) 7 days Fasted overnight Careful observation with resuscitation equipment.
Aberer W, et al. ENDA, the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003; 58:854-63

Allergy to drugs
Certain drugs cause hypersensitivity reactions more frequently

than others:
Anticonvulsants Anti-infectious agents

Radiocontrast media
Neuromuscular blocking agents (NMBA) NSAID (pyrazolones, diclofenac,..)

Special cases: corticosteroids, heparins, antineoplastic drugs

Anti-convulsants
Carbamazepine, lamotrigine, phenobarbital
Anticonvulsants can cause mild to very severe mainfestations like DHiS/DRESS and SJS/TEN Anti-convulsant hypersensitivity syndrome can occur in 1:3000 treated persons Immunogenetic risk factors were defined in Han-chinese (HLA-B*1502) Symptoms differ from drug to drug: exanthema, hepatitis, nephritis, fever, signs of capillary leak syndrome, similar to symptoms observed in a cytokine storm (compare TGN-1412 incident) Laboratory tests: lymphocytosis and high eosinophils in >70%, high cytokines (IL-5, IFN ) in serum, ALT/AST , (serum creatinine ) Often in the third week re-appearance of symptoms in the absence of drug intake: due to re-activation of HHV-6 and other herpes viruses (CMV, EBV, HHV-6,7) Treatment: corticosteroids for hepatitis; use of high dose Ig-replacement therapy (IVIG) - controversial

Anti-infectious agents
-lactams:
2-8% of hospitalized patients develop allergies (MPE > urticaria > anaphylaxis > SJS) Are haptens, able to cause all forms of drug allergies (type I IVa-d) Cross-reactivity between penicillins and cephalosporins ? 4-11% in immediate reactions with documented type I allergy Predominantly in earlier studies for 1st generation cephalosporins (cephalothin, cephaloridine) Very rare and negligible in delayed reactions Recommendation for skin testing to penicillins and suspected cephalosporin

Cross-reactivity within -lactam group

Same core structure T-cells + IgE

cefadroxil

amoxicillin

Same side chains: IgE cross-reactivity possible* T-cell cross-reactivity extremely rare

Padovan

* Blanca M, et al: Allergy 2001 E. et al. Eur J Immunol 1996 Mauri-Hellweg D et al J.I. 1996

Anti-infectious agents
Sulfonamides: e.g. sulfamethoxazole (SMX) Mainly given in combination with trimethoprim (cotrimoxazole) ~ 2-4% of hospitalized patients develop allergies, but up to 50% of HIV infected patients treated for Pneumocystis jirovecii prophylaxis (MPE > urticaria > anaphylaxis > SJS) SMX can become a hapten (SMX-NO), able to cause all forms of drug allergies (type I - IVd) T-cell reactions (exanthema IVa-IVd) mainly due to p-i concept, namely a direct stimulation of TCR by SMX

NSAID sensitivity
Incidence of aspirin hypersensitivity
General population 0.6-2.5% Adult asthmatics 4.3-11%

Clinical phenotypes
NSAID/Asprin exacerbated respiratory disease (AERD) or aspirin induced asthma (AIA) Underlying asthma, sinusitis, nasal polyposis (Widal/Samters triad) Aspirin induced urticaria/angioedema (AIU) Underlying chronic idiopathic urticaria (CIU) NSAID induced urticaria/angioedema/anaphylaxis No underlying risk factors NSAID single reactors

Genetic risk factors

HLA associations and genetic polymorphisms in aspirin-sensitive asthma and urticaria/angioedema in certain populations

NSAID sensitivity
Diagnosis Inhalational lysine aspirin challenge Oral aspirin drug provocation test Search for an alernative by DPT Not validated/investigational Skin tests Specific IgE tests Flow-CAST (Cellular antigen stimulation tests) Treatment Aspirin Desensitization for AERD Prevention Education on potentially cross-reacting NSAID Use of selective COX-2 inhibitors as alternative

Peri-operative anaphylaxis
Occur in 1 : 10,000-20,000 anesthetic procedures and in 1:6500 administrations of neuromuscular blocking agents (NMBAs) Symptoms reach from mild urticaria to death due to anaphylactic shock (3-10% of peri-operative death are due to such reactions) The severe reactions may involve only one system, most commonly the cardiovascular system About 60% of the immediate hypersensitivity reactions occurring during anesthesia are IgE-mediated But 16-50% occur in persons not previously exposed to anaesthesia 28% have recurrent symptoms in the following 8 hrs

Causes of perioperative anaphylaxis

NMBAs* Latex 50 70 % 16.7 - 22.3 % Colloids (albumin, dextran, gelatin, hetastarch 1-2% Aprotinin (polypeptide serine protease inhibitor) 0.5 - 5% Protamine < 0.5% Antiseptics (chlorhexidine, povidone) < 0.5% Dyes (patent blue, Isosulfan) and RCM: < 0.5%

Antibiotic

10 20 %

* Neuromuscular blocking agents like suxamthonium, pancuronium, vecuronium, atracurium, cis-atracurium

Skin tests in peri-operative anaphylaxis

Approximately 6 weeks after event All drugs (diluted ~1:1000), i.d. & serology, if available

The sensitivity of skin tests for NMBAs is approximately 94%

Latex skin prick test & serology

Radiocontrast Media

Iohexol a non ionic monomer

Iodixanol, non ionic dimer

Iomeprol, a non ionic monomer

Iobitridol a non ionic monomer

Differentiate between the older ionic and the newer, and better tolerated non-ionic CM, and between monomers (e.g. iohexol) and dimers (iodihexanol)

Radiocontrast media
Contrast media are widely applied (> 70 million applications/yr) They are triiodinated phenyl ring structures, rapidly excreted by the urine They cause immediate, sometimes even lethal reactions. These were more frequent with ionic CM. The newer non-ionic dimers cause less side effects (<1%), but delayed, mostly mild reactions occur with them as well (mainly with non-ionic dimers, 2-4%) About 50% of CM induced immediate and delayed reactions appear upon the first exposure Intradermal skin tests with a battery of CM can be positive with immediate and delayed reactions. The highest sensitivity is seen 2-6 months after the reaction Cross-reactivity is very common in delayed, less common in immediate reactions. Skin tests may help in the identification of an alternative (tolerated) CM.

Chemotherapeutic agents
Hypersensitivity reactions are not common except with Platinum compounds (cisplatin, carboplatin) Epipodophyllotoxins (teniposide, etoposide) Asparaginase 6-mercaptopurine Taxanes (paclitaxel) Procarbazine Doxorubicin

Mechanisms Not known, as they have generally not been evaluated Some cases may be due to non-immune mediated release of histamine or cytokines, as many patients can subsequently tolerate re-exposure after pretreatment with steroids and antihistamine, and slow readministration of the drug Some cases are immune mediated Reaction rates may vary with different forms of the drugs, e.g. pegylated
Graded re-challenge Generally successful for taxanes, less so for platinum compounds

Corticosteroids
Topical application of corticosteroids (CS) to the skin can lead to sensitization to the CS (contact dermatitis) Subsequent nasal or bronchial administration of the same or structurally related CS as well as oral application can lead to appearance of symptoms like flush, urticaria, exanthema; anaphylaxis to i.m. applied CS has been reported, but may be due to methylcellulose Patch skin tests with a battery of CS can pinpoint the relevant CS; often delayed reading (7d) is necessary, due to the immuosuppressive effect of CS In most cases a CS of another group is tolerated and can be given without problems

Corticosteroid allergy: common cross-reactivities

Structurally related CS can be grouped according to their structural similarity into groups and can also cause allergic reactions in already sensitized individuals: Budesonide may result in allergy to fluocinolone, triamcinolone, hydrocortisone-17-butyrate, methylprednisolone acetponate and prednicarbate Tixocortol-21-pivalate may result in allergy to hydrocortisone (acetate), prednisolone, dludrocortisone, methylprednisolone, hydrocortisone-17-butyrate, methylprednisolone aceponate and prednicarbate Hydrocortisone-17-butyrate allergy may result in allergy to methylprednisolone aceponate, prednicarbate, alclomethasone dipropionate, budesonide and hydrocortisone (acetate)

Multiple drug hypersensitivity

An existing contact dermatitis or previous drug allergy may be a risk factor for an allergic reaction to CM About 10% of patients with severe drug hypersensitivty may develop another drug allergy to a structurally not related compound Patients suffering from an allergy e.g. to an antibacterial drug and switched to another drug may react to the second compound (with or without detectable sensitization/skin test)

Treatment
Stop the suspected drug/ drugs Resuscitation in serious reactions ABC (airway, breathing, circulation) in anaphylaxis Drugs: Antihistamine: i/v, oral. i/m epinephrine: anaphylaxis Systemic corticosteroids: for DiHS, SJS High dose IVIG 1g/kg/d x 2 days : for early TEN/SJS overlap, TEN Emollients & Skin care Hydration and prevention of skin superinfection (TEN)

Treatment
Inpatient: observation, i/v, skin care, allergist referral Angioedema (oropharyngeal/laryngeal), anaphylaxis Severe skin: bullous drug eruption, EM/SJS/TEN Systemic symptoms: fever, lymphadenopathy, organomegaly possibly > 1 implicated drug Outpatient Urticaria/ maculopapular rash Fixed drug eruption Drug allergy without systemic symptoms When to refer to allergist Uncertain whether the reaction was drug allergy Uncertain which drug: need for re-evaluation and specific testing Desensitization

Desensitization
Making a patient tolerant to a drug he/she is allergic to When there are no reasonable alternatives Contraindicated: SJS/TEN Not contraindicated: anaphylaxis Patient still considered allergic to the drug Rapid desensitization immediate hypersensitivity: penicillin G, insulin Slow desensitization delayed hypersensitivity: allopurinol, sulphasalazine, TB drugs, SMX

Desensitization
Possible mechanisms (IgE-mediated reactions) Consumption of IgE in immune complexes Hapten inhibition Mediator depletion from mast cells and basophils Antigen specific mast cell desensitization Recent research models Cross-linking of inhibitory receptors on mast cells In-vitro desensitization of human mast cells depletes syk, an upstream signal transducing molecule necessary for IgE signalling Mechanism in delayed reactions unknown

Prevention

Patient Education Potentially cross-reacting drugs Medic Alert cards/bracelets Pharmacovigilance Notify local drug regulatory agencies Electronic Medical Records