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

Allergic Reactions to Drugs and Diagnostic Agents

Rebecca S. Gruchalla, M.D., Ph.DUT 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 ADRsType 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 ADRsType 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


• 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


• 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!!

• History!!

• History!!


• 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


• 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

0

5

10

15

20

25

30

0.5 2 4 8 16 32 64

Time after reaction

Units/

liter

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 TESTINGPredictive 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 PatientsCan 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 AllergyGeneral

• 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 ALLERGYBernstein 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 ALLERGYBernstein 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 drug2. Give cephalosporin via graded challenge (2% will react with anaphylaxis)3. Desensitize

PositiveNegative

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

therapyStark et al. J Allergy Clin Immunol 1987;79:523-32.

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 H1-

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;94189-94.

Vancomycin “Desensitization”

• Protocol– initial vancomycin infusion rate (VIR)

0.0001 mg/min– increased 3-3.3 fold q 10 min.– after VIR of 2.2-4.4 mg/min reached,

infusion kept constant– if unable to be reached, last tolerated VIR

used and dose increased over next few days


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


ACE-Inhibitor Induced Angioedema

• Can cause angioedema in 0.1-0.2%• 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

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 (SO2NH2, benzene ring)

• Some meds contain sulfur but are not sulfonamides

Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide

NonantibioticsStrom 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



• 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



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 clinicaltests support the occurrence of a drug

reaction

Non- immune ADRImmunologic reaction

suspected?

No

Management:• Modify dose• Alternative drug• Slow graded challenge• Prophylactic regimen• Patient education

Yes



Performconfirmatory

tests

Test positive?

High negative predictivevalue?

Patient maybe allergic

Patient not allergicto drug

Not Available

Available

Yes NoNo

Yes


Diagnosis of drug hypersensitivity

reaction confirmed

Patient maybe allergic

TestPositive?

MANAGEMENT

Yes


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 83:665-700, 1999.

• Gruchalla, R.S. Allergic reactions to drugs. In Frank, M, Austen, KF, Atkinson, J, Cantor, H (eds): Samter’s Immunologic Diseases. Lippincott Williams & Wilkins. 72:921-934, 2001.

• Gruchalla, R.S. Drug metabolism, danger signals and drug hypersensitivity. J Allergy Clin Immunol 108:475-478, 2001.

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

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