Allergic Reactions to Drugs and Diagnostic Agents Rebecca S. Gruchalla, M.D., Ph.D UT Southwestern Medical Center Dallas, Texas

CASE HISTORY Mr. S is a 53 y/o WM who was admitted to the day surgery unit for a RUE contracture release procedure. His PMH is remarkable for a hx of swelling after taking penicillin several years ago. The patient did well during induction, but within minutes after receiving a “test” dose of cefazolin he developed urticaria and marked hypotension that required an epinephrine infusion. The pt’s BP stabilized and the pt recovered w/o sequelae.

SCOPE OF THE PROBLEM WHO ADR Definition: “Any noxious, unintended, and undesired effect of a drug that occurs at doses used in humans for prevention, diagnosis or treatment”

CLASSIFICATION OF ADRs Type A Reactions Predictable, common and related to the pharmacologic actions of the drug; may occur in any individual

CLASSIFICATION OF ADRs Type A Reactions Toxicity - hepatic failure with high-dose acetaminophen Side effect - sedation with antihistamines Secondary effect - development of diarrhea with antibiotic tx Drug interaction - theophylline toxicity in the presence of erythromycin therapy

CLASSIFICATION OF ADRs Type B Reactions Unpredictable, uncommon and usually not related to the pharmacologic actions of the drug; occur only in susceptible individuals

CLASSIFICATION OF ADRs Type B Reactions Intolerance - tinnitus with aspirin use Idiosyncratic reaction - development of anemia with the use of oxidant drugs in the presence of G6PD deficiency Hypersensitivity (immunologic) reaction - anaphylaxis with penicillin administration Pseudoallergic (nonimmunologic) reaction - radiocontrast dye reaction

FEATURES OF ALLERGIC DRUG REACTIONS Immunologic drug reactions are preceded by a period of sensitization First dose reactions imply that the patient either was previously sensitized to the drug or that the reaction was not allergic in nature

FEATURES OF ALLERGIC DRUG REACTIONS Allergic drug reactions are restricted to a limited number of syndromes that have a known or a presumed immunopathologic basis Allergic drug reactions are temporally related to drug exposure

FEATURES OF ALLERGIC DRUG REACTIONS Immediate drug reactions may be triggered by a drug amount that is far below the therapeutic range!

CLASSIFICATION OF ALLERGIC REACTIONS TO DRUGS Gell and Coombs Classification Immediate hypersensitivity reactions Cytotoxic antibody reactions Immune complex reactions Delayed-type hypersensitivity reactions

CLASSIFICATION PROBLEMS In some instances, classification is easy In most instances, classification is difficult since the mechanism responsible for the reaction is not known Hypersensitivity reactions are uncommon, unpredictable and can not be reproduced in animal models

CLASSIFICATION PROBLEMS Most drug-induced allergic reactions can not be classified into one of the Gell and Coombs classification categories because the mechanisms responsible are not known We need to begin thinking “out of the box” Both immune and nonimmune mechanisms may be operative

EVALUATION OF THE DRUG- ALLERGIC PATIENT History!!

EVALUATION OF THE DRUG- ALLERGIC PATIENT Identify all medication usage and dosages Determine when a medication was initiated and establish a temporal relationship Determine if there was a prior hx of drug exposure Characterize the reaction type

EVALUATION OF THE DRUG- ALLERGIC PATIENT Determine if the patient has renal or hepatic disease Determine the propensity a drug has for causing a particular type of reaction Perform a thorough skin exam - urticaria?, petechia? mucous membrane involvement? Distinguish between maculopapular eruptions and urticaria

DIAGNOSTIC TESTS For Immunologically-Mediated Type B Rxns General laboratory tests (LFTs, BUN/creatinine, CBC, urinalysis, CXR) Biochemical/immunological markers that confirm the activation of certain pathways (total hemolytic complement, anti-nuclear antibodies, 24-hour urine for histamine metabolites)

TRYPTASE Selective marker of mast cells Beta-tryptase is stored in secretory granules and it is actively released when mast cells degranulate Beta-tryptase levels are elevated after anaphylaxis (>5 ng/ml) Tryptase levels should be obtained 1-2 hours after the onset of anaphylaxis

Tryptase Levels During Intraoperative Anaphylaxis Matsson et al. Agents and Actions 33:218, 1991

DIAGNOSTIC EVALUATION Is Skin Testing Useful?

DIAGNOSIS OF DRUG ALLERGY In Vivo Skin Testing Large molecular weight compounds (foreign antisera, hormones, enzymes, toxoids) Penicillin Other antibiotics?

PENICILLIN SKIN TESTING Predictive Value Positive - Immediate reactions - 67% Negative - Urticaria 98% - Anaphylaxis >99%

Penicillin Resensitization in Patients with a History of Penicillin Allergy Solensky et al, Dallas, Texas, AAAAI 2000 Up to 10% of the population reports an allergy to PCN For immediate administration of PCN, the negative predictive value of the skin test is >99% The predictive value for future courses was evaluated All 29 patients who completed the study remained PCN skin test negative after 3 courses of PCN

Penicillin-Allergic Patients Can They Receive Cephalosporins? The degree of clinical cross-reactivity between penicillins and cephalosporins is unclear In the literature, it is quoted that 10%-20% of patients with a history of PCN allergy and who are skin test positive to PCN will develop a reaction if given a cephalosporin Current reaction rates are much less

PENICILLINS AND CEPHALOSPORINS Share a Common Beta-lactam Ring Structure

Cephalosporin Allergy General Cephalosporins and penicillins have a common beta-lactam ring structure and moderate cross-reactivity has been shown in vitro. Most of the cross-reactions have involved first and second generation cephalosporins. Reactions to cephalosporins may be directed to the side chain.

Cephalosporin Allergy Special problems Carbapenems should be considered potentially cross-reactive with CS Aztreonam (monobactam) and ceftazidime share a side chain and thus, may cross- react

ADMINISTRATION OF CEPHALOSPORINS TO PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY Bernstein et al. Ann Allergy Asthma Immunol 83:665, 1999 Option 1: Give the cephalosporin directly Although only 1% will have a reaction within 24 hours, their reactions may be anaphylactic!!!

ADMINISTRATION OF CEPHALOSPORINS TO PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY Bernstein et al. Ann Allergy Asthma Immunol 83:665, 1999 Option 2: Skin test to penicillin Give cephalosporin; less than 1% will have mild reactions within 24 hrs Options: 1. Give alternate drug 2. Give cephalosporin via graded challenge (2% will react with anaphylaxis) 3. Desensitize Positive Negative

Acute Drug Desensitization Definition –process by which a drug-allergic individual is converted from a highly sensitive state to a state in which the drug is tolerated Procedure –cautious administration of incremental doses of the drug over hours to days –primarily used in IgE mediated reactions –may be employed in certain non-IgE mediated, immune reactions

Drug Desensitization IgE Sensitivity –beta-lactam antibiotics –aminoglycosides –clarithromycin –insulin –vaccines –quaternary ammonium muscle relaxants Non-IgE Sensitivity –trimethoprim- sulfamethoxazole –aspirin –vancomycin –clindamycin –anti-tubercular agents

Candidates for PCN Desensitization History of IgE mediated reaction Positive PCN skin test No alternative antibiotics available Risk of fatal allergic reaction considered less of a threat than risk of fatal outcome if beta-lactam antibiotics not used

Complications During Desensitization Pruritus Urticaria/angioedema Wheezing

Management Problems During Desensitization Doses missed during therapy –omission –loss of IV access –expired orders Drug suddenly D/C’d –misunderstandings on cross-coverage or new service Drugs withheld due to new rashes Full doses administered after long lapses in therapy Stark et al. J Allergy Clin Immunol 1987;79:

Sulfonamide Hypersensitivity Reactions Very frequent in HIV infected patients (44-70%) Clinical Features –maculopapular rash –erythroderma –fever –leukopenia –urticaria/angioedema –erythema multiforme (minor or major) –toxic epidermal necrolysis

Sulfonamides Hypersensitivity Reactions Pathophysiology –urticaria/angioedema/anaphylaxis likely IgE mediated –detected by skin test and RAST ( poor sensitivity) –maculopapular/erythroderma rash mechanism unclear –T cell mediated –IgG, IgM mediated –metabolic abnormality drug metabolites

TMP-SMX “Desensitization” ? Overall there is a lack of evidence that the morbilliform eruptions and fever due to TMP- SMX are due to IgE or non-IgE mediated mechanisms Terms other than “desensitization” may be more appropriate –graded challenge –test dosing –tolerance induction –incremental dose regimen

Vancomycin Adverse Reactions local phlebitis nephrotoxicity otic toxicity leukocytosis eosinophilia neutropenia agranulocytosis thrombocytopenia Red Man syndrome maculopapular eruption urticaria exfoliative dermatitis fever

Red Man Syndrome Constellation of symptoms –common pruritus flushing –uncommon hypotension chest discomfort Occurs in 35-90% of normal volunteers infused 1 gm vancomycin over 1 hr severity correlates with amount of histamine released into plasma severity reduced by –reducing rate to < 500 mg/hr –premedication with H 1 - antagonists

Vancomycin “Desensitization” Wong et al. Evaluated the safety and efficacy of a rapid continuous IV “desensitization” in patients with adverse reactions to vancomycin –7 patients had marked adverse reactions to vancomycin despite reducing rate and antihistamines 100% intense pruritus 71% flushing 71% urticaria 29% hypotension 29% anxiety Wong et al. J Allergy Clin Immunol 1994;

Vancomycin “Desensitization” Protocol –initial vancomycin infusion rate (VIR) mg/min –increased fold q 10 min. –after VIR of mg/min reached, infusion kept constant –if unable to be reached, last tolerated VIR used and dose increased over next few days Wong et al. J Allergy Clin Immunol 1994;

Vancomycin “Desensitization” Results –4/7 reached target VIR on 1st day –3/7 reached a threshold VIR reaction repeatedly occurred when VIR increased above threshold symptoms rapidly abated when VIR lowered –above features argue against an IgE mediated mechanism when narcotics discontinued, VIR able to be increased –Narcotics reduced threshold VIR in 5/7 patients Wong et al. J Allergy Clin Immunol 1994;

ACE-Inhibitor Induced Angioedema Can cause angioedema in % Predilection for face and upper airway Not drug specific Usually occur within first week of use, but may occur much later May also occur with ARB’s Pathophysiology not understood –Not an allergic mechanism

CASE HISTORY A 56 year old white male has a history of a pruritic rash when he took sulfamethoxazole 6 years ago. He now needs: Hydrodiuril - a thiazide diuretic Furosemide - a nonthiazide diuretic Diamox - a carbonic anhydrase inhibitor Celebrex - a Cox II inhibitor Micronase - a sulfonylurea

SULFONAMIDE ALLERGY Sulfonamide drugs are derivative of para- amino-benzoic acid They have sulfur dioxide and nitrogen groups linked to the benzene ring There is concern that sulfa allergic individuals may be sensitive to other drugs that contain these components (SO 2 NH 2, benzene ring) Some meds contain sulfur but are not sulfonamides

Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics Strom et al. NEJM 2003;349:1628 Of 969 patients with an allergic reaction after a sulfonamide antibiotic, 9.9% had an allergic reaction after receiving a sulfonamide nonantibiotic Of 19,257 who had no allergic reaction after a sulfonamide antibiotic, 1.6% had an allergic reaction after receiving a sulfonamide nonantibiotic

Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics Strom et al. NEJM 2003;349:1628 However, the risk of an allergic reaction was even greater after the receipt of a penicillin among patients with a prior reaction to a sulfonamide antibiotic

Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics Strom et al. NEJM 2003;349:1628 Conclusion Thus, while there appears to be an association between sulfonamide antimicrobial allergy and reactions to sulfonamide nonantimicrobial drugs, this association “appears to be due to a predisposition to allergic reactions rather than to cross-reactivity with sulfonamide- based drugs”

CELEBREX Celebrex is a benzenesulfonamide derivative Product labeling recommends that it not be given to sulfonamide-allergic patients Cross-reactivity has not been reported but it is a theoretical concern A retrospective meta analysis of premarketing trials compared the rate of allergic reactions to celcoxib, placebo, and other NSAIDs in pts with a history of sulfonamide allergy

CELEBREX Although sulfonamide allergy was an exclusion criterion in these studies, 135 out of 11,008 patients were found to be allergic to a sulfonamide antibiotic, furosemide, hydrochlorothiazide or a sulfonylurea Among these patients, there was no significant difference in the rate of allergic reactions to celecoxib, other NSAIDs and placebo

Algorithm For Disease Management Of Drug Hypersensitivity Patient develops a possible ADR Review of hx, records, PE and clinical tests support the occurrence of a drug reaction

Non- immune ADR Immunologic reaction suspected? No Management: Modify dose Alternative drug Slow graded challenge Prophylactic regimen Patient education Yes Algorithm For Disease Management Of Drug Hypersensitivity

Perform confirmatory tests Test positive? High negative predictive value? Patient may be allergic Patient not allergic to drug Not Available Available Yes No Yes

Algorithm For Disease Management Of Drug Hypersensitivity Diagnosis of drug hypersensitivity reaction confirmed Patient may be allergic Test Positive? MANAGEMENT Yes

Algorithm For Disease Management Of Drug Hypersensitivity MANAGEMENT: Anaphylactic reactions require prompt treatment Avoid drug if possible Consider desensitization or graded challenge Consider prophylactic regimen Future prudent use of drugs Future use of TEN/SJS-inducing drug contraindicated Patient education

References Bernstein, I.L., Gruchalla, R.S., Lee, R.E., Nicklas, R.A., Dykewicz, M.S. Disease Management of drug hypersensitivity: A practice parameter. Ann Allergy Asthma Immunol 83: , Gruchalla, R.S. Allergic reactions to drugs. In Frank, M, Austen, KF, Atkinson, J, Cantor, H (eds): Samter’s Immunologic Diseases. Lippincott Williams & Wilkins. 72: , Gruchalla, R.S. Drug metabolism, danger signals and drug hypersensitivity. J Allergy Clin Immunol 108: , 2001.