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GLORIA Module 11: Drug Allergy (Part 2) Clinical Management of Drug Allergy

GLORIA Module 11: Drug Allergy (Part 2) Clinical Management of Drug Allergy. an educational program of. Updated: June 2011. Global Resources in Allergy (GLORIA™).

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GLORIA Module 11: Drug Allergy (Part 2) Clinical Management of Drug Allergy

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  1. GLORIA Module 11:Drug Allergy (Part 2)Clinical Management of Drug Allergy an educational program of Updated: June 2011

  2. Global Resources in Allergy (GLORIA™) Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations and local training programs. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.

  3. US GLORIA Program In conjunction with the American College of Allergy, Asthma and Immunology (ACAAI), GLORIA is now presented for CME Credit in the US to Regional, State and Local Societies. The GLORIA educational materials are available for download on WAO’s website www.worldallergy.org/gloria

  4. World Allergy Organization (WAO) The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.

  5. WAO’s Mission WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

  6. GLORIA MODULE 11:Drug Allergy (Part 2)Clinical Management of Drug AllergyAuthorsWerner Pichler, SwitzerlandBernard Thong, Singapore

  7. 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

  8. Clinical features of drug hypersensitivity May be cutaneous, organ-specific, or systemic

  9. 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 ...) Drug allergy IgE IgG & Compl. T-cell

  10. immune complex blood vessel TH2 platelets TH1 IFN- Ag IL-4IL-5 eotaxin CXCL8GM-CSF PMN CTL cytokines, inflammatory mediators chemokines, cytokines, cytotoxins cytokines, inflammatory mediators Antibody mediated hypersensitivity reactions (I-III) and delayed type hypersensitivity reactions (IV a-d) Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003

  11. 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)

  12. 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

  13. 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

  14.   Immediate 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)         () () Appearance of symptoms in immediate or delayed type drug allergy

  15. 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 Allergic vs non-allergic drug hypersensitivity Drug provocation tests can be positive in allergic and non allergic reactions

  16. MC hapten- carrier 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, TNFa, Tryptase,.... * Both IgE and non-immune mediated mechanisms possible

  17. 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

  18. Anaphylaxis and anaphylactic shock

  19. 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)

  20. Exanthems T-cells recognize the drug and exert, depending on their function, a specific pathology Maculopapular exanthem (MPE) Acute generalized exanthematous pustulosis (AGEP) Bullous Exanthem

  21. 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

  22. Acute Generalized Heterogeneous Exanthematous Pustulosis (AGEP) - Patch Tests • Patch tests are frequently positive • The patch test reaction at48 hrs imitates the early phase of the disease withT-cell infiltration • After 96 hrs, pustule formation can be observed

  23. 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.

  24. Serious drug allergies Both immediate and delayed reactions may be potentially life-threatening Anaphylaxis (immediate reaction) is not the only life-threatening reaction

  25. 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 % ?

  26. 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

  27. Diagnosis of drug allergy • Can it be a drug hypersensitivity ? If so, allergic or non-allergic? • 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

  28. Identifying the responsible drug • 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

  29. 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 ) Laboratory testsfor serious reactions In late reactions certain laboratory tests are recommended to assess severity

  30. Immediate reactionsSerum 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.

  31. 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.

  32. Skin Prick Test (SPT) • Specific • Sensitive • Simple to perform • Rapid (result in 15-20 min) • Educational for patient

  33. 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.

  34. 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)

  35. Illustration of a Widely Used Assay (ImmunoCAP® System) for Allergen Specific IgE Quantification Patient IgE Allergen coupled to ImmunoCAP Conjugate; Enzyme Anti-IgE PatientIgE ab bound to ImmunoCAP allergen Fluorogenic substrate Conjugate bound to patient IgE Conjugate enzyme reacts with substrate forming a fluorescent product

  36. 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)

  37. 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%.

  38. 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

  39. 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

  40. 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, 321–328 Barbaud A. Toxicology 2005; 209:209–216

  41. 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

  42. 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.

  43. 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

  44. 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

  45. Anti-convulsants Carbamazepine, lamotrigine, phenobarbital • Anticonvulsants can cause mild tovery severemainfestations 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

  46. Anti-infectious agents b-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

  47. Cross-reactivity within b-lactam group Same core structure T-cells§ + IgE amoxicillin cefadroxil * Blanca M, et al: Allergy 2001 §Padovan E. et al. Eur J Immunol 1996 Mauri-Hellweg D et al J.I. 1996 Same side chains: IgE cross-reactivity possible* T-cell cross-reactivity extremely rare

  48. 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

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