GLORIA Module 11: Drug Allergy (Part 2)

Clinical Management of Drug Allergy

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Updated: June 2011

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GLORIA MODULE 11: Drug Allergy (Part 2)

Clinical Management of Drug Allergy

Authors Werner Pichler, Switzerland Bernard 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 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.

Immune reactant Antigen Effector

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

IgE Soluble antigen Mast-cell activation Ag

Type II

IgG Cell- or matrix associated antigen FcR + cells (phagocytes, NK cells) platelets

Type III

IgG Soluble antigen FcR + cells Complement blood vessel immune complex IFN (T H 

Type IV a Type IV b Type IV c

, TNFα 1 cells) IL-5, IL-4/IL-13 (T H 2 cells) Perforin/ GranzymeB (CTL) 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

Type IV d

CXCL-8. GM-CSF, IL-17 (?) (T-cells) Antigen presented by cells or direct T cell stimulation Macrophage activation Eosinophils T cells Neutrophils T H 2 IFN  T H 1 IL-4 IL-5 eotaxin CTL CXCL8 GM-CSF PMN Example of hypersen-sitivity reaction Allergic rhinitis, asthma, systemic anaphylaxis Some drug allergies (e.g., penicillin) Serum sickness, Arthus reaction Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003 chemokines, cytokines, cytotoxins cytokines, inflammatory mediators Tuberculin reaction, contact dermatitis (with IVc) Chronic asthma, chronic allergic rhinitis, maculo papular exanthema with eosinophilia Contact dermatitis, maculopapular and bullous exanthema, hepatitis cytokines, inflammatory mediators AGEP, Behçet disease

• • • • • • • • •

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

(exanthema)

16 14 12 10 8 6 4 2 0 1

    

3 5

 

12 9 13 1 13 3 13 5 13 7 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

Allergic vs non-allergic drug hypersensitivity

Allergic Non-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) 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

MC

hapten carrier

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, TNF a , Tryptase,....

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 (>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 Mortality 10 – 30 % • 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 % 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.

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

Documentation of acute stage: 2.

• • • • • 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.

5.

6.

7.

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) •

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 tests for serious reactions

Immediate reactions

• Serum tryptase • Serum histamine

Delayed reactions

• Complete blood count: eosinophilia and lymphocytosis, leukocytosis • Liver function tests:   GT, ALP ALT, AST, •  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 0 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 Quantification ® System) for Allergen Specific IgE 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 65 80% 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 35–80%) • 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: 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 reactions Patch 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, 321–328 Barbaud 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 SJS/TEN

very severe

mainfestations like DHiS/DRESS and 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 1 st (cephalothin, cephaloridine) generation cephalosporins – 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 * 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 like suxamthonium, 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

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 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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