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
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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.

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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

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CLASSIFICATION OF ADRs

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

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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

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CLASSIFICATION OF ADRs

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

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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

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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

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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

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FEATURES OF ALLERGIC DRUG REACTIONS

• Immediate drug reactions may be triggered by a
  drug amount that is far below the therapeutic
  range!

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CLASSIFICATION OF ALLERGIC REACTIONS TO DRUGS

• Gell and Coombs Classification
• Immediate hypersensitivity reactions
• Cytotoxic antibody reactions
• Immune complex reactions
• Delayed-type hypersensitivity reactions

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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

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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

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EVALUATION OF THE DRUG-ALLERGIC PATIENT

• History!!
• History!!
• History!!

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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

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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

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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)

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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

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Tryptase Levels During Intraoperative
AnaphylaxisMatsson et al. Agents and Actions
33218, 1991
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DIAGNOSTIC EVALUATION

• Is Skin Testing Useful?

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DIAGNOSIS OF DRUG ALLERGYIn Vivo Skin Testing

• Large molecular weight compounds (foreign
  antisera, hormones, enzymes, toxoids)
• Penicillin
• Other antibiotics?

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PENICILLIN SKIN TESTINGPredictive Value

• Positive
• - Immediate reactions - 67
• Negative
• - Urticaria 98
• - Anaphylaxis gt99

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Penicillin Resensitization in Patients with a
History of Penicillin AllergySolensky 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

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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

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PENICILLINS AND CEPHALOSPORINSShare a Common
Beta-lactam Ring Structure
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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.

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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

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ADMINISTRATION OF CEPHALOSPORINS TO PATIENTS WITH
A HISTORY OF PENICILLIN ALLERGYBernstein 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!!!
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ADMINISTRATION OF CEPHALOSPORINS TO PATIENTS WITH
A HISTORY OF PENICILLIN ALLERGYBernstein 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
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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

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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

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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

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Complications During Desensitization

• Pruritus
• Urticaria/angioedema
• Wheezing

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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.
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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

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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

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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

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Vancomycin Adverse Reactions

• local phlebitis
• nephrotoxicity
• otic toxicity
• leukocytosis
• eosinophilia
• neutropenia
• agranulocytosis
• thrombocytopenia

• Red Man syndrome
• maculopapular eruption
• urticaria
• exfoliative dermatitis
• fever

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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

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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.
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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.
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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

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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

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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

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Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide NonantibioticsStrom
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

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Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide NonantibioticsStrom
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

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Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide NonantibioticsStrom
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

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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

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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

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

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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.