allergic reactions to drugs and diagnostic agents rebecca s. gruchalla, m.d., ph.d ut southwestern...
TRANSCRIPT
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
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!!
• History!!
• 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
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
Wong et al. J Allergy Clin Immunol 1994;94189-94.
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;94189-94.
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
Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide
NonantibioticsStrom 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
NonantibioticsStrom 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 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
Algorithm For Disease Management Of Drug Hypersensitivity
Algorithm For Disease Management Of Drug Hypersensitivity
Performconfirmatory
tests
Test positive?
High negative predictivevalue?
Patient maybe allergic
Patient not allergicto drug
Not Available
Available
Yes NoNo
Yes
Algorithm For Disease Management Of Drug Hypersensitivity
Diagnosis of drug hypersensitivity
reaction confirmed
Patient maybe allergic
TestPositive?
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 83:665-700, 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.