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Drug Hypersensitivity
朱士傑
三軍總醫院 風濕免疫過敏科
Drug reaction: encompass all adverse
events related to drug administration,
regardless of etiology.
 Drug hypersensitivity: defined as an
immune-mediated response to a drug
agent in a sensitized patient.(5-10%)
 Drug allergy: restricted specifically to a
reaction mediated by IgE.

Adverse Drug Reactions (WHO)
• All non-therapeutic consequences of a drug
except treatment failure, intentional or
accidental poisoning and drug abuse
• ADRs cause 75,000 to 106,000 deaths /
year
• The most common iatrogenic illness
Common and Predictable ADRs
Type A
• Overdosage
• Side effects (immediate and delayed)
• Secondary / indirect effects (related to
drug alone: diarrhea from disturbance of
microbial flora; related to drug and
disease: maculopapular rash to ampicillin
with viral infections)
• Drug - drug interactions
• 75-80%
Less Common Unpredictable ADRs
Type B
• Immune and certain non-immune
(pseudo allergy, idiosyncrasy,
intolerance) responses account for
25% of all ADRs
• Estimated deaths range from
18,750 to 26,500 / year
Definitions
 Idiosyncrasy and intolerance are non-
immune ADRs
 Pseudoallergic (anaphylactoid) responses
are non-immunologic and caused by
several mechanisms (i.e., direct release of
cell mediators; activation of complement)
• Drug intolerance: an undesired drug effect
produced by the drug at therapeutic or
subtherapeutic dosages
• Idiosyncratic reactions: uncharacteristic
reactions that are not explicable in terms of
the known pharmacologic actions of the
drug
Drug Hypersensitivity
Classification Strategies
• Type of immune response (IgE,
cytotoxic, immune complex, cell
mediated)
• Predominant organ involved
• Chemical structure of drug
Drug Hypersensitivity
Risk Factors
• Drug specific (chemical properties,
dose, route, duration of Rx, number
of exposures)
Drug Hypersensitivity
Clinical Diagnosis
• History is crucial
• Exam of affected organ
systems
• General laboratory tests
• Specific immunologic tests
• Diagnosis often presumptive
Drug Hypersensitivity
Treatment
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Stop the drug
Anaphylaxis regimen
Glucocorticosteroids for immune
complex and other severe multisystem syndromes
Desensitization
Graded challenges
Drug Hypersensitivity Prevention
•
•
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Ascertain host risks
Avoid cross-reactive drugs
Use of predictive skin tests
Prudent use of drugs
Preferential use of oral drugs
Drug Hypersensitivity
IgE Mediated Reactions
• Clinical presentation:
urticaria / angioedema / anaphylaxis
• Caused by many drugs and biologics
• Most often due to ß-lactam antibiotics
• Less common with many non-ß-lactam
antibiotics
• May be caused by excipients
Drug Hypersensitivity
Ig Mediated Cytoxic Reactions
• Serious and life-threatening
• Tend to occur after large doses
• Immunohemolytic anemia (e.g.,
penicillin)
• Immune thrombocytopenia (e.g.,
quinidine)
• Immune neutropenia (e.g., thiouracils)
Drug Hypersensitivity
Immune Complex Reactions
• Drugs often implicated: penicillin,
sulfonamides, phenytoin
• Symptoms occur 1-3 weeks after last
dose
• IgE antibodies sometimes present
• Glucocorticosteroids may be needed
Drug Hypersensitivity
Cell-Mediated Reactions
• Allergic contact dermatitis
• Photoallergic dermatitis
• Late cutaneous morbilliform
and bullous reactions
Beta-lactam IgE-Mediated Hypersensitivity
Key Points
• Skin tests with proper major and minor
determinants have excellent negative predictive
value of penicillin specific IgE and clinical
hypersensitivity
• A positive skin test denotes the presence of
penicillin-specific IgE antibodies
• If penicillin is required in patients with positive
skin tests and there is no available alternative,
desensitization should be performed
Beta-lactam IgE-Mediated Hypersensitivity
Key Points
(continued)
• Penicillin cross reacts with semi-synthetic,
penicillins and carbapenem (imipenem)
• There is no cross reaction with aztreonam
• Cross reactivity with first generation
cephalosporins may be 6-10%
• Cross reactivity with 2d and 3d generation
cephalosporins may be <2%
• Anaphylaxis to any beta lactam agent
possible
Drug Hypersensitivity
Non Beta-lactam Antibiotics
• Incidence 1-3% but may be higher in some
groups
• Trimethoprim-sulfamethoxazole, especially in
AIDS
• Vancomycin - red man syndrome, IgEmediated
• Aminoglycosides - rare
• Quinolones - pseudoallergic
Drug Hypersensitivity
Miscellaneous Syndromes
• Hypersensitivity vasculitis
– Many drugs, hematopoietic growth
factors, cytokines and interferons
are associated with vasculitis of skin
and visceral organs
– Some drugs (eg, hydralazine and
procainamide) may induce a lupuslike syndrome
Drug Hypersensitivity
Miscellaneous Syndromes
• Pulmonary drug hypersensitivity
– include lupus-like reactions, alveolar or interstitial
pneumonitis, non-cardiogenic pulmonary edema,
granulomatosis and fibrosis.
– The Churg-Strauss syndrome has been reported in an
increasing number of patients receiving
glucocorticosteroids alone, leukotriene receptor
antagonists for asthma with or without
glucocorticosteroids and macrolide antibiotics. A
causal relationship between these drugs and the
Churg-Strauss syndrome has not been established
Drug Hypersensitivity
Miscellaneous Syndromes
•
Anti-convulsant hypersensitivity syndrome
– occur after varying periods of exposure to anticonvulsant
medications.
– inherited deficiency of epoxide hydrolase, an enzyme required for
the metabolism of arene oxide intermediates produced during
hepatic metabolism of anticonvulsant drugs
– fever, a maculopapular rash and generalized lymphadenopathy
– induced by phenytoin, carbamazepine, or phenobarbital and
cross-reactivity may occur among all anticonvulsants that produce
toxic arene oxide metabolites.
– pseudolymphoma
– induced by phenytoin, carbamazepine, or phenobarbital and
cross-reactivity may occur among all anticonvulsants that produce
toxic arene oxide metabolites
– Valproic acid, gabapentin, and lamatrogine may be acceptable
therapeutic alternatives
Drug Hypersensitivity
Miscellaneous Syndromes
• Immunologic Hepatitis
– may occur after sensitization to
para-amino-salacylic acid,
sulfonamides, and phenothiazines.
Drug Hypersensitivity
Miscellaneous Syndromes
• Immunologic nephropathy
– may present as interstitial nephritis (a
classical example is methicillin) or as a
membranous glomerulonephritis (eg, gold
salts, penicillamine
Miscellaneous Syndromes
• Blistering Disorders
(continued)
– Erythema multiforme minor
• appears to be a cell-mediated
hypersensitivity reaction associated with
viruses, other infectious agents, and drugs.
• manifested by pleomorphic cutaneous
eruptions, at times bullous.
• Target lesions are also characteristic.
•
If a drug cause is suspected, the drug
should be stopped immediately and the
addition of glucocorticosteroids may be
necessary.
Antihistamines may help pruritus.
Early treatment (prednisone 1
mg/kg/qd) may prevent progression to
the more serious erythema multiforme
major/Stevens-Johnson syndrome.

• Blistering Disorders
(continued)
– Erythema multiforme major/ Stevens-Johnson
syndrome
• more than a hundred drugs implicated as causes
• In a large prospective cohort study, drugs
associated with a high relative risk of developing SJS
or TEN were sulfonamides, cephalosporins,
imidazole agents, and oxicam derivatives; while
drugs in the moderate risk category included
quinolones, carbamazepine, phenytoin, valproic
acid, and glucocorticosteroids.
–Ocular involvement may be particularly serious. Liver,
kidney and lungs may be involved singly or in combination
–As soon as the diagnosis is established, the suspected drug
should be stopped immediately
–target and bullous lesions primarily involving the extremities
and mucous membranes are characteristic of EMM while the
features of SJS are confluent purpuric macules on face and
trunk and severe, explosive mucosal erosions, usually at more
than one mucosal surface, that are accompanied by high fever
and severe constitutional symptoms.
–The use of glucocorticosteroid therapy is controversial.
– If it is started, it should probably be started early in the
course of the disease and very large doses (eg, 80 to 160 mg)
of intravenous methylprednisolone (every 4 to 6 hours) should
be used.
–If this treatment is started too late in the course of the disease
(ie, 3 to 4 days after onset), it is possible that TEN could
supervene, in which case systemic glucocorticosteroids are
contraindicated.
• Blistering Disorders
– Toxic epidermal necrolysis
• Stevens-Johnson syndrome and TEN are
(continued)
probably part of a single spectrum
• If epidermal detachment is less than 10%, the
disease is probably Stevens-Johnson but when
epidermal detachment reaches 30% or more,
the diagnosis of toxic epidermal necrolysis is
probable.
• In cases with detachment of 10% to 30% of
the epidermis, the two syndromes are
overlapping.
•TEN almost always drug-induced
•manifested by widespread areas of confluent erythema
followed by epidermal necrosis and detachment with severe
mucosal involvement
•Significant loss of skin equivalent to a third degree burn
occurs.
•Glucocorticosteroids are contraindicated in this condition
which must be managed in a burn unit
• significant risk of infection and mortality
Recently,
intravenous gamma globulin (0.2 to
0.75 g/kg body weight per day for 4 days)
provided dramatic improvement with complete
recovery in some TEN patients with increased
levels of Fas ligand
TEN should be distinguished from the scalded
skin syndrome, a disorder caused by
staphylococcal bacterial toxin and characterized
by the massive skin cleavage and separation in
the uppermost epidermis
scalded skin syndrome
Miscellaneous Syndromes
• “Serum-sickness-like reactions”
– cefaclor, cefprozil
– characterized primarily by severe erythema
multiforme and arthralgias.
– no evidence of an antibody-mediated basis for
this reaction
– So far, this reaction has only been reported
with these drugs
– affected patients later have tolerated nonrelated cephalosporins.
Such
patients should avoid the offending
drugs and other cephalosporins with
similar side chains
"Serum-sickness-like" reactions to
cefaclor appear to result from altered
metabolism of the parent drug resulting in
reactive intermediate compounds

This altered metabolism can often be
documented in a parent of the patient.

Alert Clinicians That a Drug Induced Cutaneous Eruption
May Be Serious