Beruflich Dokumente
Kultur Dokumente
Clinical Management of
Drug Allergy
an educational program of
Sponsored by:
Authors
Werner Pichler, Switzerland
Bernard Thong, Singapore
Learning Objectives
Immune IgE IgG IgG IFNγ , TNFα IL-5, IL-4/IL-13 Perforin/ CXCL-8.
reactant (TH1 cells) (TH2 cells) GranzymeB GM-CSF, IL-17 (?)
(CTL) (T-cells)
Antigen Soluble antigen Cell- or matrix- Soluble antigen Antigen presented Antigen presented Cell-associated Antigen presented
associated antigen by cells or direct T by cells or direct T antigen or direct T by cells or direct T
cell stimulation cell stimulation cell stimulation cell stimulation
Effector Mast-cell activation FcR+ cells FcR+ cells Macrophage Eosinophils T cells Neutrophils
(phagocytes, NK Complement activation
cells)
immune complex
blood
vessel
TH2
platelets IFN-γ
TH1
Ag
IL-4 CXCL8 PMN
IL-5 eotaxin
CTL GM-CSF
cytokines,
chemokines, cytokines,
inflammatory
cytokines, cytotoxins inflammatory
mediators
mediators
Example of Allergic rhinitis, asthma, Some drug allergies Serum sickness, Arthus Tuberculin reaction, Chronic asthma, Contact dermatitis, AGEP,
hypersen- systemic anaphylaxis (e.g., penicillin) reaction contact dermatitis (with chronic allergic rhinitis, maculopapular and Behçet disease
sitivity reaction IVc) maculo-papular bullous exanthema,
exanthema with hepatitis
eosinophilia
Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003
Drug allergy: Heterogeneous
clinical manifestations &
pathophysiology
• Urticaria, anaphylaxis
• Blood cell dyscrasia
• Vasculitis
• Maculopapular exanthem
• Bullous or pustular
exanthems (AGEP)
• Stevens-Johnson Syndrome
(SJS), toxic-epidermal
necrolysis (TEN)
• Hepatitis, interstitial
nephritis, pneumopathy
• Drug induced autoimmunity
(SLE, pemphigus ...)
• Drug induced
hypersensitivity syndrome
(DiHS/DRESS)
Sub-classification of drug
allergy
• According to
– Timing of onset
• Symptoms start <1hr after administration (immediate)
vs
• >1hr (often 6hr) after application (delayed)
- Immune mechanism
• Gell & Coombs classification, type I-IVa-d
- Combined
• Immediate and IgE mediated
• Delayed and T-cell mediated (rarely IgG)
7
1
12
13
13
13
13
symptoms
(urticaria, anaphylaxis)
45
40
35
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ (↓) (↓)
Delayed type: 30
25
Sensitization and 20
15
Maculopapular exanthem
(MPE) Acute
Bullous
Exanthem generalized
exanthematous
pustulosis
(AGEP)
Acute Generalized
Exanthematous Pustulosis
(AGEP)
Clinical manifestations
• Generalized, sterile
pustules
• Fever (>38°C)
• Leukocytosis
Aetiology
• Mainly drugs (~90%)
• Rapid onset (3-4d)
• Mercury (~10%)
• Acute enteroviral infection
Acute Generalized
Heterogeneous
Exanthematous Pustulosis
(AGEP) - Patch Tests
• Patch tests are frequently positive
• The patch test reaction at 48 hrs
imitates the early phase of the
disease with T-cell infiltration
• After 96 hrs, pustule formation
can be observed
Delayed reactions:
danger symptoms and signs
• Extensive, confluent infiltrated exanthema
• Bullae, pustules
• Nikolsky sign
• Erythrodermia
• Painful skin
• Mucosal affection
• Facial oedema
• Lymphadenopathy
• Constitutional symptoms (higher fever, malaise,
fatigue): Look carefully if any of these signs is present.
Stop all ongoing drugs. Do liver, renal and blood tests.
Serious drug allergies
• Specific
• Sensitive
• Simple to perform
• Rapid (result in 15-20 min)
• Educational for patient
Intradermal Skin Test (IDT)
• Results
– Reported as kU/L
– Positive ≥ 0.7 kU/L (Class 2)
Illustration of a Patient IgE
Allergen Specific
IgE Quantification Patient IgE ab bound to
ImmunoCAP allergen
Fluorogenic substrate
Conjugate bound to
patient IgE
Courtesy: Pichler WJ
Drug Provocation Tests
• Indications
(DPT)
– Exclude hypersensitivity in non-suggestive history or non-
specific symptoms (± SBDC,DBPCDC)
– Provide safe pharmacologically and/or structurally non-
related drugs in proven hypersensitivity e.g. beta-lactam
antibiotics
– Exclude cross-reactivity of related drugs in proven
hypersensitivity e.g. cephalosporin in a penicillin allergic
– Definitive diagnosis in suggestive history with negative,
non-conclusive or non-available allergological tests
• Contraindications
– Pregnant women
– Co-morbidity where DPT may provoke situation beyond
medical control e.g.
• Acute infection
• Uncontrolled asthma
• Underlying cardiac, hepatic, renal disease
– Immunobullous drug eruptions
– Severe systemic initial reaction.
Drug Provocation Tests
(DPT)
Same core
structure
T-cells§ + IgE
cefadroxil amoxicillin
Same side chains: IgE cross-reactivity possible* * Blanca M, et al: Allergy 2001
Padovan E. et al. Eur J Immunol 1996
§
• Clinical phenotypes
– NSAID/Asprin exacerbated respiratory disease (AERD) or aspirin
induced asthma (AIA)
• Underlying asthma, sinusitis, nasal polyposis (Widal/Samter’s
triad)
– Aspirin induced urticaria/angioedema (AIU)
• Underlying chronic idiopathic urticaria (CIU)
– NSAID induced urticaria/angioedema/anaphylaxis
• No underlying risk factors
– NSAID single reactors
Iohexol Iodixanol,
a non ionic monomer non ionic dimer
Iomeprol, Iobitridol
a non ionic monomer a non ionic monomer
Differentiate between the older ionic and the newer, and better tolerated
non-ionic CM, and between monomers (e.g. iohexol) and dimers (iodihexanol)
Radiocontrast media
• Contrast media are widely applied (> 70 million applications/yr)
• They are triiodinated phenyl ring structures, rapidly excreted by
the urine
• They cause immediate, sometimes even lethal reactions. These
were more frequent with ionic CM. The newer non-ionic dimers
cause less side effects (<1%), but delayed, mostly mild reactions
occur with them as well (mainly with non-ionic dimers, 2-4%)
• About 50% of CM induced immediate and delayed reactions
appear upon the first exposure
• Intradermal skin tests with a battery of CM can be positive with
immediate and delayed reactions. The highest sensitivity is seen
2-6 months after the reaction
• Cross-reactivity is very common in delayed, less common in
immediate reactions. Skin tests may help in the identification of an
alternative (tolerated) CM.
Chemotherapeutic agents
• Hypersensitivity reactions are not common except with
– Platinum compounds (cisplatin, carboplatin)
– Epipodophyllotoxins (teniposide, etoposide)
– Asparaginase
– 6-mercaptopurine
– Taxanes (paclitaxel)
– Procarbazine
– Doxorubicin
• Mechanisms
– Not known, as they have generally not been evaluated
– Some cases may be due to non-immune mediated release of histamine or
cytokines, as many patients can subsequently tolerate re-exposure after
pretreatment with steroids and antihistamine, and slow readministration of
the drug
– Some cases are immune mediated
– Reaction rates may vary with different forms of the drugs, e.g. pegylated
• Graded re-challenge
– Generally successful for taxanes, less so for platinum compounds
Corticosteroids
• Topical application of corticosteroids (CS) to the skin can lead to
sensitization to the CS (contact dermatitis)
• Subsequent nasal or bronchial administration of the same or
structurally related CS as well as oral application can lead to
appearance of symptoms like flush, urticaria, exanthema;
anaphylaxis to i.m. applied CS has been reported, but may be
due to methyl-cellulose
• Patch skin tests with a battery of CS can pinpoint the relevant
CS; often delayed reading (7d) is necessary, due to the
immuosuppressive effect of CS
• In most cases a CS of another group is tolerated and can be
given without problems
Corticosteroid allergy:
common cross-reactivities
• Structurally related CS can be grouped according to their
structural similarity into groups and can also cause allergic
reactions in already sensitized individuals:
• Budesonide may result in allergy to fluocinolone, triamcinolone,
hydrocortisone-17-butyrate, methylprednisolone acetponate and
prednicarbate
• Tixocortol-21-pivalate may result in allergy to hydrocortisone
(acetate), prednisolone, dludrocortisone, methylprednisolone,
hydrocortisone-17-butyrate, methylprednisolone aceponate and
prednicarbate
• Hydrocortisone-17-butyrate allergy may result in allergy to
methylprednisolone aceponate, prednicarbate, alclomethasone
dipropionate, budesonide and hydrocortisone (acetate)
Multiple drug
hypersensitivity
• Drugs:
– Antihistamine: i/v, oral.
– i/m epinephrine: anaphylaxis
– Systemic corticosteroids: for DiHS, SJS
– High dose IVIG 1g/kg/d x 2 days : for early TEN/SJS overlap,
TEN
• Outpatient
– Urticaria/ maculopapular rash
– Fixed drug eruption
– Drug allergy without systemic symptoms
• Patient Education
– Potentially cross-reacting drugs
– Medic Alert cards/bracelets
• Pharmacovigilance
– Notify local drug regulatory
agencies
• Electronic Medical Records
World Allergy Organization
(WAO)
For more information on the World Allergy
Organization (WAO), please visit
www.worldallery.org or contact the:
WAO Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: info@worldallergy.org