GLORIA Module 11:Drug Allergy (Part 2)

Clinical Management of Drug Allergy

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GLORIA MODULE 11:Drug Allergy (Part 2)

Clinical Management of Drug Allergy

AuthorsWerner Pichler, SwitzerlandBernard Thong, Singapore

Learning Objectives

• Understand the clinical features of drug allergy in relation to the underlying pathogenetic mechanisms

• Understand the principles in the clinical diagnosis of drug allergy

• Understand the principles of diagnostic and provocation tests

• Manage drug allergies

Clinical features of drug

hypersensitivityMay be cutaneous,

organ-specific,or systemic

Drug allergy

• 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.

T-cell

Antibody mediated hypersensitivity reactions

(I-III) and delayed type hypersensitivity reactions (IV a-d)

Type I Type II Type IIIType IV a Type IV b Type IV c

Type IV d

Immune reactant

IgE IgG IgGIFN, TNFα(TH1 cells)

IL-5, IL-4/IL-13(TH2 cells)

Perforin/GranzymeB

(CTL)

CXCL-8. GM-CSF, IL-17

(?) (T-cells)

Antigen Soluble antigenCell- or matrix-

associated antigen

Soluble antigen

Antigen presented by

cells or direct T cell stimulation

Antigen presented by

cells or direct T cell stimulation

Cell-associated antigen or direct T cell stimulation

Antigen presented by cells or direct T cell stimulation

EffectorMast-cell activation

FcR+ cells (phagocytes, NK

cells)

FcR+ cellsComplement

Macrophage activation

Eosinophils T cells Neutrophils

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, maculo-papular exanthema with eosinophilia

Contact dermatitis,maculopapular and bullous exanthema,hepatitis

AGEP,Behçet disease

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

Ag

platelets

blood vessel

immune complex

TH1

chemokines, cytokines, cytotoxins

cytokines, inflammatory

mediators

CTL

cytokines, inflammatory

mediators

IFN-TH2

IL-4IL-5 eotaxin PMNCXCL8

GM-CSF

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 allergyImmediate type:“silent” sensitization, well tolerated; at re-exposure quick development of symptoms(urticaria, anaphylaxis)

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

05

1015202530354045

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

024

68

1012

1416

() ()

Allergic vs non-allergic drug hypersensitivity

Allergic

Immune reactions (T-cells, IgE,IgG against a drug/metabolitewith 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 thedrug detectable, symptoms canoccur 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*

Histamine, LT, TNF,Tryptase,....

hapten-carrier

MC

* Both IgE and non-immune mediated mechanisms possible

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

Clinical Symptoms and Signs

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)

ExanthemsT-cells recognize the drug and exert, depending on their

function, a specific pathology

BullousExanthem

Acute generalized exanthematous pustulosis (AGEP)

Maculopapular exanthem(MPE)

Acute Generalized Exanthematous Pustulosis

(AGEP)

Clinical manifestations• Generalized, sterile

pustules• Fever (>38°C)• 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• 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

Mortality

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. Can it be a drug hypersensitivity ? If so, allergic or non-allergic?

1. 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

2. Identifying the responsible drug

Identifying the responsible drug

1. History

2. Experience with the drug: books indicating specific side effects of drugs

3. Definition of presumed pathomechanism (IgE, T-cell, IgG)

4. Skin tests with non toxic preparations of the drug – Skin prick test (SPT); Intradermal test (IDT) – Late reading IDT and patch tests

5. 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

6. Lymphocyte transformation/activation test

7. Drug provocation tests (where 4-6 not available/ not validated)• The responsible drug is identified by a combination of history, clinical experience of

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

Laboratory testsfor 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 reactionsSerum tryptase

0 30 60 90 120 150 180 210 240 270 300 330

Plasma histamine

Serum tryptase

24-hr Urinary histamine metabolite

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

Immediate reactionsSkin 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 reactionsDrug 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)

Patient IgE

Allergen coupled toImmunoCAP

Conjugate;Enzyme Anti-IgE

Patient IgE ab bound toImmunoCAP allergen

Fluorogenic substrate

Conjugate bound topatient IgE

Conjugate enzyme reacts withsubstrate forming a fluorescent product

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

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 65-80% of penicillin allergic individuals.

– NSAIDs: sensitivity 71-76%– Positive Test: > 15% CD63+ (Stimulation Index ≥ 2)

Immediate reactionsCAST

• 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 35–80%)• Specificity between 79 and 89%.

Delayed reactionsLymphocyte 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: 809–820

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: 809–820

Delayed reactionsPatch tests

• Drug patch tests are positive in 32–50% 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, 321–328Barbaud A. Toxicology 2005; 209:209–216

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

amoxicillincefadroxil

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

Same core structureT-cells§ + IgE

* Blanca M, et al: Allergy 2001 §Padovan 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/Samter’s

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* 50 – 70 %

• Latex 16.7 - 22.3 %

• Antibiotic 10 – 20 %

* Neuromuscular blocking agents likesuxamthonium, pancuronium, vecuronium,atracurium, cis-atracurium

• 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%

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

Iomeprol, a non ionic monomer

Iohexola non ionic monomer

Iobitridola non ionic monomer

Iodixanol, non ionic dimer

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

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 methyl-cellulose

• 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

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