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Allergic Reactions to Drugs and Diagnostic Agents

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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 ... – PowerPoint PPT presentation

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Title: Allergic Reactions to Drugs and Diagnostic Agents


1
Allergic Reactions to Drugs and Diagnostic Agents
Rebecca S. Gruchalla, M.D., Ph.D UT Southwestern
Medical Center Dallas, Texas
2
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 pts BP stabilized and the pt
    recovered w/o sequelae.

3
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

4
CLASSIFICATION OF ADRs
  • Type A Reactions
  • Predictable, common and related to the
    pharmacologic actions of the drug may occur in
    any individual

5
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

6
CLASSIFICATION OF ADRs
  • Type B Reactions
  • Unpredictable, uncommon and usually not related
    to the pharmacologic actions of the drug occur
    only in susceptible individuals

7
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

8
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

9
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

10
FEATURES OF ALLERGIC DRUG REACTIONS
  • Immediate drug reactions may be triggered by a
    drug amount that is far below the therapeutic
    range!

11
CLASSIFICATION OF ALLERGIC REACTIONS TO DRUGS
  • Gell and Coombs Classification
  • Immediate hypersensitivity reactions
  • Cytotoxic antibody reactions
  • Immune complex reactions
  • Delayed-type hypersensitivity reactions

12
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

13
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

14
EVALUATION OF THE DRUG-ALLERGIC PATIENT
  • History!!
  • History!!
  • History!!

15
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

16
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

17
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)

18
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 (gt5 ng/ml)
  • Tryptase levels should be obtained 1-2 hours
    after the onset of anaphylaxis

19
Tryptase Levels During Intraoperative
Anaphylaxis Matsson et al. Agents and Actions
33218, 1991
20
DIAGNOSTIC EVALUATION
  • Is Skin Testing Useful?

21
DIAGNOSIS OF DRUG ALLERGY In Vivo Skin Testing
  • Large molecular weight compounds (foreign
    antisera, hormones, enzymes, toxoids)
  • Penicillin
  • Other antibiotics?

22
PENICILLIN SKIN TESTING Predictive Value
  • Positive
  • - Immediate reactions - 67
  • Negative
  • - Urticaria 98
  • - Anaphylaxis gt99

23
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 gt99
  • 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

24
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

25
PENICILLINS AND CEPHALOSPORINS Share a Common
Beta-lactam Ring Structure
26
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.

27
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

28
ADMINISTRATION OF CEPHALOSPORINS TO PATIENTS WITH
A HISTORY OF PENICILLIN ALLERGY Bernstein et al.
Ann Allergy Asthma Immunol 83665, 1999
Option 1 Give the cephalosporin
directly Although only 1 will have a reaction
within 24 hours, their reactions may be
anaphylactic!!!
29
ADMINISTRATION OF CEPHALOSPORINS TO PATIENTS WITH
A HISTORY OF PENICILLIN ALLERGY Bernstein et al.
Ann Allergy Asthma Immunol 83665, 1999
Positive
Option 2 Skin test to penicillin
Negative
Options 1. Give alternate drug 2. Give
cephalosporin via graded challenge (2 will
react with anaphylaxis) 3. Desensitize
Give cephalosporin less than 1 will have mild
reactions within 24 hrs
30
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

31
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

32
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

33
Complications During Desensitization
  • Pruritus
  • Urticaria/angioedema
  • Wheezing

34
Management Problems During Desensitization
  • Doses missed during therapy
  • omission
  • loss of IV access
  • expired orders
  • Drug suddenly D/Cd
  • 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
198779523-32.
35
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

36
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

37
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

38
Vancomycin Adverse Reactions
  • local phlebitis
  • nephrotoxicity
  • otic toxicity
  • leukocytosis
  • eosinophilia
  • neutropenia
  • agranulocytosis
  • thrombocytopenia
  • Red Man syndrome
  • maculopapular eruption
  • urticaria
  • exfoliative dermatitis
  • fever

39
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 lt 500 mg/hr
  • premedication with H1-antagonists

40
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 199494189-94.
41
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 199494189-94.
42
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 199494189-94.
43
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44
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 ARBs
  • Pathophysiology not understood
  • Not an allergic mechanism

45
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

46
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

47
Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide Nonantibiotics Strom
et al. NEJM 20033491628
  • 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

48
Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide Nonantibiotics Strom
et al. NEJM 20033491628
  • 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

49
Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide Nonantibiotics Strom
et al. NEJM 20033491628
  • 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

50
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

51
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

52
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
53
Algorithm For Disease Management Of Drug
Hypersensitivity
Immunologic reaction suspected?
No
Non- immune ADR
  • Management
  • Modify dose
  • Alternative drug
  • Slow graded challenge
  • Prophylactic regimen
  • Patient education

Yes
54
Algorithm For Disease Management Of Drug
Hypersensitivity
Not Available
Perform confirmatory tests
High negative predictive value?
No
No
Yes
Patient may be allergic
Patient not allergic to drug
Test positive?
Available
Yes
55
Algorithm For Disease Management Of Drug
Hypersensitivity
Test Positive?
Patient may be allergic
Yes
Diagnosis of drug hypersensitivity reaction
confirmed
MANAGEMENT
56
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

57
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 83665-700, 1999.
  • Gruchalla, R.S. Allergic reactions to drugs. In
    Frank, M, Austen, KF, Atkinson, J, Cantor, H
    (eds) Samters Immunologic Diseases. Lippincott
    Williams Wilkins. 72921-934, 2001.
  • Gruchalla, R.S. Drug metabolism, danger signals
    and drug hypersensitivity. J Allergy Clin Immunol
    108475-478, 2001.
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