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 DRUGALLERGIC PATIENT
• History!!
• History!!
• History!!
EVALUATION OF THE DRUGALLERGIC 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 DRUGALLERGIC 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
30
Units/liter
25
20
15
10
5
0
0.5
2
4
8
16
Time after reaction
32
64
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 crossreact
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
Negative
Option 2:
Skin test to penicillin
Give cephalosporin;
less than 1% will have
mild reactions within 24 hrs
Positive
Options:
1. Give alternate drug
2. Give cephalosporin
via graded challenge
(2% will react with
anaphylaxis)
3. Desensitize
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
• Non-IgE Sensitivity
– beta-lactam
– trimethoprimantibiotics
sulfamethoxazole
– aminoglycosides
– aspirin
– clarithromycin
– vancomycin
– insulin
– clindamycin
– vaccines
– anti-tubercular
– quaternary
agents
ammonium muscle
relaxants
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;79:523-32.
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 TMPSMX 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 H1antagonists
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 paraamino-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
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 sulfonamidebased 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
Algorithm For Disease Management Of
Drug Hypersensitivity
Immunologic
reaction
suspected?
Yes
No
Non- immune ADR
Management:
• Modify dose
• Alternative drug
• Slow graded challenge
• Prophylactic regimen
• Patient education
Algorithm For Disease Management Of
Drug Hypersensitivity
Not Available
Perform
confirmatory
tests
High negative predictive
value?
No
Test
positive?
Yes
Yes
Patient not allergic
to drug
No
Patient may
be allergic
Algorithm For Disease Management
Of Drug Hypersensitivity
Test
Positive?
Yes
Patient may
be allergic
Diagnosis of drug
hypersensitivity
reaction confirmed
MANAGEMENT
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 108:475478, 2001.