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Drug Hypersensitivity 朱士傑 三軍總醫院 風濕免疫過敏科 Drug reaction: encompass all adverse events related to drug administration, regardless of etiology. Drug hypersensitivity: defined as an immune-mediated response to a drug agent in a sensitized patient.(5-10%) Drug allergy: restricted specifically to a reaction mediated by IgE. Adverse Drug Reactions (WHO) • All non-therapeutic consequences of a drug except treatment failure, intentional or accidental poisoning and drug abuse • ADRs cause 75,000 to 106,000 deaths / year • The most common iatrogenic illness Common and Predictable ADRs Type A • Overdosage • Side effects (immediate and delayed) • Secondary / indirect effects (related to drug alone: diarrhea from disturbance of microbial flora; related to drug and disease: maculopapular rash to ampicillin with viral infections) • Drug - drug interactions • 75-80% Less Common Unpredictable ADRs Type B • Immune and certain non-immune (pseudo allergy, idiosyncrasy, intolerance) responses account for 25% of all ADRs • Estimated deaths range from 18,750 to 26,500 / year Definitions Idiosyncrasy and intolerance are non- immune ADRs Pseudoallergic (anaphylactoid) responses are non-immunologic and caused by several mechanisms (i.e., direct release of cell mediators; activation of complement) • Drug intolerance: an undesired drug effect produced by the drug at therapeutic or subtherapeutic dosages • Idiosyncratic reactions: uncharacteristic reactions that are not explicable in terms of the known pharmacologic actions of the drug Drug Hypersensitivity Classification Strategies • Type of immune response (IgE, cytotoxic, immune complex, cell mediated) • Predominant organ involved • Chemical structure of drug Drug Hypersensitivity Risk Factors • Drug specific (chemical properties, dose, route, duration of Rx, number of exposures) Drug Hypersensitivity Clinical Diagnosis • History is crucial • Exam of affected organ systems • General laboratory tests • Specific immunologic tests • Diagnosis often presumptive Drug Hypersensitivity Treatment Stop the drug Anaphylaxis regimen Glucocorticosteroids for immune complex and other severe multisystem syndromes Desensitization Graded challenges Drug Hypersensitivity Prevention • • • • • Ascertain host risks Avoid cross-reactive drugs Use of predictive skin tests Prudent use of drugs Preferential use of oral drugs Drug Hypersensitivity IgE Mediated Reactions • Clinical presentation: urticaria / angioedema / anaphylaxis • Caused by many drugs and biologics • Most often due to ß-lactam antibiotics • Less common with many non-ß-lactam antibiotics • May be caused by excipients Drug Hypersensitivity Ig Mediated Cytoxic Reactions • Serious and life-threatening • Tend to occur after large doses • Immunohemolytic anemia (e.g., penicillin) • Immune thrombocytopenia (e.g., quinidine) • Immune neutropenia (e.g., thiouracils) Drug Hypersensitivity Immune Complex Reactions • Drugs often implicated: penicillin, sulfonamides, phenytoin • Symptoms occur 1-3 weeks after last dose • IgE antibodies sometimes present • Glucocorticosteroids may be needed Drug Hypersensitivity Cell-Mediated Reactions • Allergic contact dermatitis • Photoallergic dermatitis • Late cutaneous morbilliform and bullous reactions Beta-lactam IgE-Mediated Hypersensitivity Key Points • Skin tests with proper major and minor determinants have excellent negative predictive value of penicillin specific IgE and clinical hypersensitivity • A positive skin test denotes the presence of penicillin-specific IgE antibodies • If penicillin is required in patients with positive skin tests and there is no available alternative, desensitization should be performed Beta-lactam IgE-Mediated Hypersensitivity Key Points (continued) • Penicillin cross reacts with semi-synthetic, penicillins and carbapenem (imipenem) • There is no cross reaction with aztreonam • Cross reactivity with first generation cephalosporins may be 6-10% • Cross reactivity with 2d and 3d generation cephalosporins may be <2% • Anaphylaxis to any beta lactam agent possible Drug Hypersensitivity Non Beta-lactam Antibiotics • Incidence 1-3% but may be higher in some groups • Trimethoprim-sulfamethoxazole, especially in AIDS • Vancomycin - red man syndrome, IgEmediated • Aminoglycosides - rare • Quinolones - pseudoallergic Drug Hypersensitivity Miscellaneous Syndromes • Hypersensitivity vasculitis – Many drugs, hematopoietic growth factors, cytokines and interferons are associated with vasculitis of skin and visceral organs – Some drugs (eg, hydralazine and procainamide) may induce a lupuslike syndrome Drug Hypersensitivity Miscellaneous Syndromes • Pulmonary drug hypersensitivity – include lupus-like reactions, alveolar or interstitial pneumonitis, non-cardiogenic pulmonary edema, granulomatosis and fibrosis. – The Churg-Strauss syndrome has been reported in an increasing number of patients receiving glucocorticosteroids alone, leukotriene receptor antagonists for asthma with or without glucocorticosteroids and macrolide antibiotics. A causal relationship between these drugs and the Churg-Strauss syndrome has not been established Drug Hypersensitivity Miscellaneous Syndromes • Anti-convulsant hypersensitivity syndrome – occur after varying periods of exposure to anticonvulsant medications. – inherited deficiency of epoxide hydrolase, an enzyme required for the metabolism of arene oxide intermediates produced during hepatic metabolism of anticonvulsant drugs – fever, a maculopapular rash and generalized lymphadenopathy – induced by phenytoin, carbamazepine, or phenobarbital and cross-reactivity may occur among all anticonvulsants that produce toxic arene oxide metabolites. – pseudolymphoma – induced by phenytoin, carbamazepine, or phenobarbital and cross-reactivity may occur among all anticonvulsants that produce toxic arene oxide metabolites – Valproic acid, gabapentin, and lamatrogine may be acceptable therapeutic alternatives Drug Hypersensitivity Miscellaneous Syndromes • Immunologic Hepatitis – may occur after sensitization to para-amino-salacylic acid, sulfonamides, and phenothiazines. Drug Hypersensitivity Miscellaneous Syndromes • Immunologic nephropathy – may present as interstitial nephritis (a classical example is methicillin) or as a membranous glomerulonephritis (eg, gold salts, penicillamine Miscellaneous Syndromes • Blistering Disorders (continued) – Erythema multiforme minor • appears to be a cell-mediated hypersensitivity reaction associated with viruses, other infectious agents, and drugs. • manifested by pleomorphic cutaneous eruptions, at times bullous. • Target lesions are also characteristic. • If a drug cause is suspected, the drug should be stopped immediately and the addition of glucocorticosteroids may be necessary. Antihistamines may help pruritus. Early treatment (prednisone 1 mg/kg/qd) may prevent progression to the more serious erythema multiforme major/Stevens-Johnson syndrome. • Blistering Disorders (continued) – Erythema multiforme major/ Stevens-Johnson syndrome • more than a hundred drugs implicated as causes • In a large prospective cohort study, drugs associated with a high relative risk of developing SJS or TEN were sulfonamides, cephalosporins, imidazole agents, and oxicam derivatives; while drugs in the moderate risk category included quinolones, carbamazepine, phenytoin, valproic acid, and glucocorticosteroids. –Ocular involvement may be particularly serious. Liver, kidney and lungs may be involved singly or in combination –As soon as the diagnosis is established, the suspected drug should be stopped immediately –target and bullous lesions primarily involving the extremities and mucous membranes are characteristic of EMM while the features of SJS are confluent purpuric macules on face and trunk and severe, explosive mucosal erosions, usually at more than one mucosal surface, that are accompanied by high fever and severe constitutional symptoms. –The use of glucocorticosteroid therapy is controversial. – If it is started, it should probably be started early in the course of the disease and very large doses (eg, 80 to 160 mg) of intravenous methylprednisolone (every 4 to 6 hours) should be used. –If this treatment is started too late in the course of the disease (ie, 3 to 4 days after onset), it is possible that TEN could supervene, in which case systemic glucocorticosteroids are contraindicated. • Blistering Disorders – Toxic epidermal necrolysis • Stevens-Johnson syndrome and TEN are (continued) probably part of a single spectrum • If epidermal detachment is less than 10%, the disease is probably Stevens-Johnson but when epidermal detachment reaches 30% or more, the diagnosis of toxic epidermal necrolysis is probable. • In cases with detachment of 10% to 30% of the epidermis, the two syndromes are overlapping. •TEN almost always drug-induced •manifested by widespread areas of confluent erythema followed by epidermal necrosis and detachment with severe mucosal involvement •Significant loss of skin equivalent to a third degree burn occurs. •Glucocorticosteroids are contraindicated in this condition which must be managed in a burn unit • significant risk of infection and mortality Recently, intravenous gamma globulin (0.2 to 0.75 g/kg body weight per day for 4 days) provided dramatic improvement with complete recovery in some TEN patients with increased levels of Fas ligand TEN should be distinguished from the scalded skin syndrome, a disorder caused by staphylococcal bacterial toxin and characterized by the massive skin cleavage and separation in the uppermost epidermis scalded skin syndrome Miscellaneous Syndromes • “Serum-sickness-like reactions” – cefaclor, cefprozil – characterized primarily by severe erythema multiforme and arthralgias. – no evidence of an antibody-mediated basis for this reaction – So far, this reaction has only been reported with these drugs – affected patients later have tolerated nonrelated cephalosporins. Such patients should avoid the offending drugs and other cephalosporins with similar side chains "Serum-sickness-like" reactions to cefaclor appear to result from altered metabolism of the parent drug resulting in reactive intermediate compounds This altered metabolism can often be documented in a parent of the patient. Alert Clinicians That a Drug Induced Cutaneous Eruption May Be Serious