GLORIA Module 11:
Drug Allergy (Part 2)
Clinical Management of Drug
Allergy
an educational program of
Updated: June 2011
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GLORIA MODULE 11:
Drug Allergy (Part 2)
Clinical Management of Drug
Allergy
Authors
Werner Pichler, Switzerland
Bernard Thong, Singapore
Learning Objectives
• Understand the clinical features of drug allergy in
relation to the underlying pathogenetic mechanisms
• Understand the principles in the clinical diagnosis of
drug allergy
• Understand the principles of diagnostic and
provocation tests
• Manage drug allergies
Clinical features of drug
hypersensitivity
May be cutaneous,
organ-specific,
or systemic
Drug allergy
•
•
•
•
•
T-cell
•
Maculopapular exanthem (MPE)
Bullous exanthem
Stevens-Johnson Syndrom (SJS),
toxic-epidermal necrolysis (TEN)
Acute generalized exanthematous
pustulosis (AGEP)
Drug induced hypersensitivity
syndrome (DiHS), or drug
reaction with eosinophilia and
systemic symptoms (DRESS)
(Interstitial) nephritis, pancreatitis,
colitis, pneumonitis, hepatitis
•
•
•
•
Urticaria, angioedema,
anaphylaxis, bronchospasm
Blood cell dyscrasia,
hemolytic anaemia,
thrombocytopenia,
agranulocytosis
Vasculitis
Drug induced autoimmunity
(SLE, pemphigus ...)
IgE
IgG
&
Compl.
Antibody mediated hypersensitivity reactions
(I-III) and delayed type hypersensitivity
reactions (IV a-d)
Type I
Type II
Type III
Type IV a
Type IV b
Type IV c
Type IV d
Immune
reactant
IgE
IgG
IgG
IFN, TNFα
(TH1 cells)
IL-5, IL-4/IL-13
(TH2 cells)
Perforin/
GranzymeB
(CTL)
CXCL-8.
GM-CSF, IL-17 (?)
(T-cells)
Antigen
Soluble antigen
Cell- or matrixassociated antigen
Soluble antigen
Antigen presented by
cells or direct T cell
stimulation
Antigen presented by
cells or direct T cell
stimulation
Cell-associated antigen
or direct T cell
stimulation
Antigen presented by
cells or direct T cell
stimulation
Mast-cell activation
FcR+ cells
(phagocytes, NK
cells)
FcR+ cells
Complement
Macrophage
activation
Eosinophils
T cells
Neutrophils
Effector
blood
vessel
immune complex
platelets
IFN-
Ag
TH2
TH1
IL-4
IL-5
chemokines, cytokines,
cytotoxins
Example of
hypersen-sitivity
reaction
Allergic rhinitis, asthma,
systemic anaphylaxis
Some drug allergies (e.g.,
penicillin)
Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003
Serum sickness, Arthus
reaction
Tuberculin reaction,
contact dermatitis (with
IVc)
eotaxin
CTL
PMN
cytokines, inflammatory
mediators
cytokines, inflammatory
mediators
Chronic asthma, chronic
allergic rhinitis, maculopapular exanthema with
eosinophilia
CXCL8
GM-CSF
Contact dermatitis,
maculopapular and
bullous exanthema,
hepatitis
AGEP,
Behçet disease
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)
Correlating the clinical manifestations with the
immununological mechanisms
Timing of onset
Within 1(-2)* hrs: immediate reactions, mainly IgE
mediated;
Urticaria, angioedema, bronchospasm, anaphylaxis,
and anaphylaxis related symptoms
After 1(-2)** hr (often > 6hrs - weeks): delayed
reactions, mainly T cell, occasionally IgG mediated:
often, but not always skin symptoms
*) the onset of IgE mediated reactions can occasionally occur later,
particularly with oral drugs
**) the onset of T-cell mediated reactions can occasionally occur early,
particularly with previous exposure to the drug
Appearance of symptoms in immediate
or delayed type drug allergy

1 2 3
4 5 6
7 8
13
7
13
5
13
3
13
1
12
9

5
Delayed type:
Sensitization and symptoms often
at 8th – 10th day of therapy
(exanthema)
45
40
35
30
25
20
15
10
5
0

3
16
14
12
10
8
6
4
2
0
1
Immediate type:
“silent” sensitization,
well tolerated;
at re-exposure quick
development of symptoms
(urticaria, anaphylaxis)
() ()
9 10 11 12 13 14 15 16 17
Allergic vs non-allergic
drug hypersensitivity
Allergic
Non-allergic
Immune reactions (T-cells, IgE,
IgG against a drug/metabolite
with exanthema, urticaria, etc.)
• Highly specific
• Dependent of structure
• Can be dangerous, severe (IgE & T
cell reactions!)
• Cross-reactions to structurally
related compounds
• IgE to drug occasionally detectable
(skin tests, IgE-serology)
No immune reaction against the
drug detectable, symptoms can
occur at the first contact
• Activation of immunological
effector cells (mast-cells, basophil
leukocytes, etc)
• Cross-reactions due to function
of drug, not structure
• Skin tests and serology negative
Drug provocation tests can be positive in allergic and
non allergic reactions
Allergic or
Non-allergic drug hypersensitivity
Drug-specific IgE with:
• penicillin/cephalosporin, pyrazolones*
quinolones*, (recombinant) proteins
MC
haptencarrier
Non-immune hypersensitivty reaction with:
• NSAID (acetylsalicylic acid, diclofenac*, .…)
radio contrast media*, muscle relaxants*,
gelatine-infusions*
* Both IgE and non-immune mediated mechanisms
possible
Histamine, LT, TNFa,
Tryptase,....
Clinical Symptoms and Signs
Type I (IgE mediated)
Allergy or non-immune
hypersensitivity reaction
• rapidly appearing urticaria
• rapidly appearing angioedema,
mostly periorbital, oral, genital
swellings, with moderate pruritus,
in association with generalized
urticaria
• gastrointestinal symptoms:
cramps, diarrhoea, vomiting
• anaphylaxis and anaphylactic
shock
Anaphylaxis and anaphylactic shock
Delayed reactions
•
•
•
•
Due to drug specific T cells
T-cells secrete different cytokines
The cytokines activate and recruit distinct effector cells
Cytotoxic mechanisms are always involved, in some
severe reactions (SJS/TEN) even dominating the
clinical symptoms
• Similar mechanism in skin as in internal organs (e.g.
interstitial nephritis)
Exanthems
T-cells recognize the drug and exert, depending on their function, a specific
pathology
Bullous
Exanthem
Maculopapular exanthem
(MPE)
Acute 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
Both immediate and delayed reactions may be
potentially life-threatening
Anaphylaxis (immediate reaction) is not the only
life-threatening reaction
Mortality in severe, delayed drug
hypersensitivity reactions
Mortality
• Stevens - Johnson Syndrome (SJS) & toxic epidermal
necrolysis (TEN): bullous exanthema and mucosal affection
• DRESS (DHiS): Drug reaction with eosinophilia and systemic
symptoms (often hepatitis, sometimes pancreatitis, interstitial
lung disease, colitis, myocarditis, pleuritis, pericarditis,
nephritis …)
• AGEP (acute generalized exanthematous pustulosis)
• Isolated hepatitis, interstitial nephritis, interstitial lung disease,
pancreatitis
10 – 30 %
10 %
5%
?
Drugs with potential for serious allergies
• Immediate reactions (anaphylaxis)
– -lactam-antibiotics, pyrazolone, neuromuscular
blocking agents, radiocontrast media
• Delayed reactions (drug-induced hypersensitivity
syndromes)
– Antiepileptics: carbamazepine, lamotrigine,
phenobarbital
– Allopurinol
– Sulfonamide/Sulfasalazine
– Nevirapine, Abacavir
– Certain quinolones
– Minocyclin, diltiazem
Diagnosis of drug allergy
1.
Can it be a drug hypersensitivity ? If so, allergic or nonallergic?
1.
Documentation of acute stage:
•
•
•
•
•
2.
Documentation of the case (semiology, chronology, all drugs
taken)
Documentation of the severity of symptoms, including
laboratory analysis (suspected serious reactions)
Establish temporal relationship of drug intake to appearance
of symptoms
Risk factors (underlying disease)
Rule out possible differential diagnosis
Identifying the responsible drug
Identifying the responsible drug
1.
2.
3.
4.
5.
6.
7.
History
Experience with the drug: books indicating specific side effects of drugs
Definition of presumed pathomechanism (IgE, T-cell, IgG)
Skin tests with non toxic preparations of the drug
– Skin prick test (SPT); Intradermal test (IDT)
– Late reading IDT and patch tests
Serology/specific IgE
– Drug specific IgE (available for few drugs only)
– Basophil activation tests (in theory available for many drugs)
– Coombs-test in the presence of drug in hemolytic anaemia
Lymphocyte transformation/activation test
Drug provocation tests (where 4-6 not available/ not validated)
• The responsible drug is identified by a combination of history, clinical experience of
drug imputability and targeted tests
• Skin and laboratory tests are performed 6 weeks after the acute stage
• Type of test depending on whether diagnosing immediate or delayed reactions
Laboratory tests
for serious reactions
Immediate reactions
• Serum tryptase
• Serum histamine
Delayed reactions
• Complete blood count:
eosinophilia and lymphocytosis,
leukocytosis
• Liver function tests:  ALT, AST,
GT, ALP
•  Serum creatinine
• Urine microscopy and dipstick:
nephritis, proteinuria
• ( CRP )
In late reactions certain laboratory tests are recommended to assess severity
Immediate reactions
Serum tryptase
Plasma histamine
Serum tryptase
24-hr Urinary histamine metabolite
0
30
60
90
120
150
180
210 240
270
300
330
An elevated level supports a diagnosis of anaphylaxis.
Normal levels do not exclude anaphylaxis.
Immediate reactions
Skin prick and intradermal tests
• For IgE-mediated reactions
• Skin prick test (SPT), Intradermal test (IDT)
• Sensitive & specific
– Sensitivity
• 70% if penicilloyl polylysine (PPL), minor
determinant mix (MDM), amoxicillin (AX) and
ampicillin (AMP) all tested
– Specificity for most -lactams 97-99%
• E.g. -lactam penicillins, cephalosporins, anaesthetic
agents.
Skin Prick Test (SPT)
•
•
•
•
Specific
Sensitive
Simple to perform
Rapid (result in 15-20
min)
• Educational for patient
Intradermal Skin Test (IDT)
• More sensitive than skin prick test
• May induce false positive
reactions
• May induce systemic reactions
• Should be done only if skin prick
test is negative and allergen is
highly suspect.
Immediate reactions
Drug specific IgE Tests
• Commercially available
– Phadia CAP®/ ImmunoCAP (fluorescent enzyme
immunoassay, FEIA)
– Penicilloyl G, penicilloyl V, suxamethonium
• Less sensitive and more expensive compared to skin testing
– Sensitivity for penicillins/ amoxycillin from 38-54%
– Specificity for penicillins/ amoxicillin from 87-100%
• Results
– Reported as kU/L
– Positive ≥ 0.7 kU/L (Class 2)
Illustration of a Widely
Used Assay
(ImmunoCAP® System)
for Allergen Specific IgE
Quantification
Patient IgE
Allergen coupled to
ImmunoCAP
Conjugate;
Enzyme Anti-IgE
Patient IgE ab bound to
ImmunoCAP allergen
Fluorogenic substrate
Conjugate bound to
patient IgE
Conjugate enzyme reacts with
substrate forming a fluorescent
product
Immediate reactions
Flow – CAST
• Flow cytometric basophil activation test (FAST, FLOW-CAST or
BASOTEST)
– Based on the flow cytometric evaluation of CD63 on blood
basophils, an activation molecule appearing following incubation of
blood basophils with drugs or other allergens in vitro
–  -lactams:
• Sensitivity 50%, specificity 93% when compared with FEIA
• Greater sensitivity and specificity than FEIA (37.9% and 86.7%
respectively)
• Combination of FAST and FEIA allows identification of 6580% of penicillin allergic individuals.
– NSAIDs: sensitivity 71-76%
– Positive Test: > 15% CD63+ (Stimulation Index ≥ 2)
Immediate reactions
CAST
• Cellular Allergen Stimulation test (CAST)-ELISA
– Sulphidoleukotrienes (LTC4 and its metabolites LTD4
and LTE4) produced upon in vitro stimulation of blood
leukocytes (predominantly basophils) by drugs are
quantitatively measured
–  -lactams:
• Sensitivity 46% (range 35–80%)
• Specificity between 79 and 89%.
Delayed reactions
Lymphocyte transformation test (LTT)
• Measures the proliferation of T cells to a drug in vitro
• Advantage:
– Applicable to many different drugs with different
immune reactions, as drug-specific T cell are almost
always involved in drug hypersensitivity reactions
• Disadvantages:
– Test per se is rather cumbersome and technically
demanding
– Sensitivity is limited
Picher WJ, et al. Allergy 2004: 59: 809–820
LTT
LTT frequently positive (>50%)
•
Generalized maculopapular exanthema
•
Bullous exanthema
•
Acute generalized exathematous pustulosis (AGEP)
•
DHS/drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS)
•
Anaphylaxis (generalized, severe symptoms)
LTT occasionally positive
•
Hepatitis (dependent on type of drug)
•
Nephritis (dependent on type of drug)
•
Urticaria, angioedema
•
Interstitial lung disease*
•
Pancreatitis*
LTT rarely positive (<10%)
•
Toxic epidermal necrolysis (TEN)
•
Vasculitis
•
Macular exanthema (without T-cell infiltration)
•
Guillain-Barre syndrome
•
Blood dyscrasia-like idiopathic thrombocytopenic purpura (ITP)
•
Haemolytic anaemia
•
Fixed drug eruption.
Picher WJ, et al. Allergy 2004: 59: 809–820
Delayed reactions
Patch tests
• Drug patch tests are positive in 32–50% of patients who
have developed a cutaneous drug eruption
• Advantages
– Usually positive in AGEP, maculopapular rash,
photodermatoses, lichenoid rash, fixed drug eruption
– Frequently positive for betalactam antibiotics, especially
amoxicillin, cotrimoxazole, corticosteroids, heparin
derivatives, pristinamycin, carbamazepine, diltiazem,
diazepam, hydroxyzine, pseudoephedrine, tetrazepam
• Disadvantages
– Low sensitivity (at best 50%)
– Lack of standardized test reagents.
Barbaud A, et al. Contact Dermatitis, 2001, 45, 321–328
Barbaud A. Toxicology 2005; 209:209–216
Acute Generalized 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.
Courtesy: Pichler WJ
Drug Provocation Tests (DPT)
•
Indications
– 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)
• Risks/benefits explained to patient
• Informed consent
• Cessation of antihistamine
– short-acting (chlorpheniramine, hydroxyzine)
3 days
– long-acting (cetirizine, loratidine, fexofenadine)
7 days
• Fasted overnight
• Careful observation with resuscitation equipment.
Aberer W, et al. ENDA, the EAACI interest group on drug hypersensitivity. Drug provocation testing in the
diagnosis of drug hypersensitivity reactions: general considerations.
Allergy 2003; 58:854-63
Allergy to drugs
Certain drugs cause hypersensitivity reactions more
frequently
than others:
• Anticonvulsants
• Anti-infectious agents
• Radiocontrast media
• Neuromuscular blocking agents (NMBA)
• NSAID (pyrazolones, diclofenac,..)
Special cases: corticosteroids, heparins, antineoplastic drugs
Anti-convulsants
Carbamazepine, lamotrigine, phenobarbital
•
•
•
•
•
•
•
Anticonvulsants can cause mild to very severe mainfestations like DHiS/DRESS and
SJS/TEN
Anti-convulsant hypersensitivity syndrome can occur in 1:3000 treated persons
Immunogenetic risk factors were defined in Han-chinese (HLA-B*1502)
Symptoms differ from drug to drug: exanthema, hepatitis, nephritis, fever, signs of
capillary leak syndrome, similar to symptoms observed in a cytokine storm (compare
TGN-1412 incident)
Laboratory tests: lymphocytosis and high eosinophils in >70%, high cytokines (IL-5,
IFN ) in serum, ALT/AST ↑ ↑, (serum creatinine ↑)
Often in the third week re-appearance of symptoms in the absence of drug intake:
due to re-activation of HHV-6 and other herpes viruses (CMV, EBV, HHV-6,7)
Treatment: corticosteroids for hepatitis; use of high dose Ig-replacement therapy
(IVIG) - controversial
Anti-infectious agents
-lactams:
• 2-8% of hospitalized patients develop allergies (MPE > urticaria >
anaphylaxis > SJS)
• Are haptens, able to cause all forms of drug allergies (type I – IVa-d)
• Cross-reactivity between penicillins and cephalosporins ?
– 4-11% in immediate reactions with documented type I allergy
– Predominantly in earlier studies for 1st generation cephalosporins
(cephalothin, cephaloridine)
– Very rare and negligible in delayed reactions
– Recommendation for skin testing to penicillins and suspected
cephalosporin
Cross-reactivity within -lactam group
Same core
structure
T-cells§ + IgE
cefadroxil
amoxicillin
Same side chains: IgE cross-reactivity possible*
T-cell cross-reactivity extremely rare
* Blanca M, et al: Allergy 2001
E. et al. Eur J Immunol 1996
Mauri-Hellweg D et al J.I. 1996
§Padovan
Anti-infectious agents
Sulfonamides: e.g. sulfamethoxazole (SMX)
– Mainly given in combination with trimethoprim
(cotrimoxazole)
– ~ 2-4% of hospitalized patients develop allergies, but up
to 50% of HIV infected patients treated for Pneumocystis
jirovecii prophylaxis (MPE > urticaria > anaphylaxis > SJS)
– SMX can become a hapten (SMX-NO), able to cause all
forms of drug allergies (type I - IVd)
– T-cell reactions (exanthema IVa-IVd) mainly due to p-i
concept, namely a direct stimulation of TCR by SMX
NSAID sensitivity
• Incidence of aspirin hypersensitivity
– General population 0.6-2.5%
– Adult asthmatics 4.3-11%
• 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
• Genetic risk factors
– HLA associations and genetic polymorphisms in aspirin-sensitive asthma and
urticaria/angioedema in certain populations
NSAID sensitivity
• Diagnosis
– Inhalational lysine aspirin challenge
– Oral aspirin drug provocation test
– Search for an alernative by DPT
– Not validated/investigational
• Skin tests
• Specific IgE tests
• Flow-CAST (Cellular antigen stimulation tests)
• Treatment
– Aspirin “Desensitization” for AERD
• Prevention
– Education on potentially cross-reacting NSAID
– Use of selective COX-2 inhibitors as alternative
Peri-operative anaphylaxis
• Occur in 1 : 10,000-20,000 anesthetic procedures and in 1:6500
administrations of neuromuscular blocking agents (NMBAs)
• Symptoms reach from mild urticaria to death due to anaphylactic
shock (3-10% of peri-operative death are due to such reactions)
• The severe reactions may involve only one system, most commonly
the cardiovascular system
• About 60% of the immediate hypersensitivity reactions occurring
during anesthesia are IgE-mediated
• But 16-50% occur in persons not previously exposed to anaesthesia
• 28% have recurrent symptoms in the following 8 hrs
Causes of perioperative
anaphylaxis
• NMBAs*
• Latex
50 – 70 %
16.7 - 22.3 %
• Antibiotic
10 – 20 %
* Neuromuscular blocking agents like
suxamthonium, pancuronium, vecuronium,
atracurium, cis-atracurium
• Colloids (albumin, dextran, gelatin,
hetastarch
1-2%
• Aprotinin (polypeptide serine
protease inhibitor)
0.5 - 5%
• Protamine
< 0.5%
• Antiseptics (chlorhexidine,
povidone)
< 0.5%
• Dyes (patent blue, Isosulfan) and
RCM:
< 0.5%
Skin tests in peri-operative
anaphylaxis
• Approximately 6 weeks after event
• All drugs (diluted ~1:1000), i.d. & serology, if available
– The sensitivity of skin tests for NMBAs is approximately
94%
• Latex skin prick test & serology
Radiocontrast media
Iohexol
a non ionic monomer
Iomeprol,
a non ionic monomer
Iodixanol,
non ionic dimer
Iobitridol
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 methylcellulose
• 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
• An existing contact dermatitis or previous drug allergy may be a
risk factor for an allergic reaction to CM
• About 10% of patients with severe drug hypersensitivty may
develop another drug allergy to a structurally not related
compound
• Patients suffering from an allergy e.g. to an antibacterial drug and
switched to another drug may react to the second compound
(with or without detectable sensitization/skin test)
Treatment
• Stop the suspected drug/ drugs
• Resuscitation in serious reactions
– ABC (airway, breathing, circulation) in anaphylaxis
• 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
• Emollients & Skin care
• Hydration and prevention of skin superinfection (TEN)
Treatment
• Inpatient: observation, i/v, skin care, allergist referral
– Angioedema (oropharyngeal/laryngeal), anaphylaxis
– Severe skin: bullous drug eruption, EM/SJS/TEN
– Systemic symptoms: fever, lymphadenopathy, organomegaly
– possibly > 1 implicated drug
• Outpatient
– Urticaria/ maculopapular rash
– Fixed drug eruption
– Drug allergy without systemic symptoms
• When to refer to allergist
– Uncertain whether the reaction was drug allergy
– Uncertain which drug: need for re-evaluation and specific testing
– Desensitization
Desensitization
•
•
•
•
•
•
Making a patient tolerant to a drug he/she is allergic to
When there are no reasonable alternatives
Contraindicated: SJS/TEN
Not contraindicated: anaphylaxis
Patient still considered allergic to the drug
Rapid desensitization
– immediate hypersensitivity: penicillin G, insulin
• Slow desensitization
– delayed hypersensitivity: allopurinol, sulphasalazine, TB
drugs, SMX
Desensitization
• Possible mechanisms (IgE-mediated reactions)
– Consumption of IgE in immune complexes
– Hapten inhibition
– Mediator depletion from mast cells and basophils
– Antigen specific mast cell desensitization
• Recent research models
– Cross-linking of inhibitory receptors on mast cells
– In-vitro desensitization of human mast cells depletes syk,
an upstream signal transducing molecule necessary for
IgE signalling
• Mechanism in delayed reactions unknown
Prevention
• 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