GLORIA Module 11:

Drug Allergy (Part 2)

Clinical Management of
Drug Allergy
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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
• Maculopapular exanthem
(MPE) • Urticaria, angioedema,
• Bullous exanthem anaphylaxis, IgE
• Stevens-Johnson Syndrom bronchospasm
(SJS), toxic-epidermal
necrolysis (TEN)
• Acute generalized • Blood cell dyscrasia,
exanthematous pustulosis hemolytic anaemia,
(AGEP) thrombocytopenia, IgG
T-cell • Drug induced agranulocytosis &
hypersensitivity syndrome
(DiHS), or drug reaction • Vasculitis Compl.
with eosinophilia and
systemic symptoms • Drug induced
(DRESS) autoimmunity (SLE,
• (Interstitial) nephritis, pemphigus ...)
pancreatitis, colitis,
pneumonitis, hepatitis
 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 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)

• 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
↓↓
16
Immediate type: 14
12
“silent” sensitization, 10
↓↓↓↓↓
8
well tolerated; 6
4
at re-exposure quick 2
0
development of

7
1

12

13

13

13

13
symptoms
(urticaria, anaphylaxis)
45
40
35
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ (↓) (↓)
Delayed type: 30
25

Sensitization and 20
15

symptoms often at 8th – 10

5

10th day of therapy 0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
(exanthema)
 Allergic vs non-allergic
drug hypersensitivity
Allergic Non-allergic

Immune reactions (T-cells, IgE, No immune reaction against the

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)
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:
MC
• penicillin/cephalosporin, pyrazolones*
quinolones*, (recombinant) proteins
hapten-
carrier
Non-immune hypersensitivty
reaction with:
• NSAID (acetylsalicylic acid,
diclofenac*, .…)
radio contrast media*, muscle Histamine, LT, TNFα ,
Both IgE and non-immune mediated mechanisms Tryptase,....
relaxants*, gelatine-infusions*
ossible
 Clinical symptoms and
Type I (IgE mediated)
signs
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
 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

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

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 10 – 30 %
necrolysis (TEN): bullous exanthema and mucosal
affection

• DRESS (DHiS): Drug reaction with eosinophilia and 10 %

systemic symptoms (often hepatitis, sometimes
pancreatitis, interstitial lung disease, colitis,
myocarditis, pleuritis, pericarditis, nephritis …)

• AGEP (acute generalized exanthematous pustulosis)

5%
• Isolated hepatitis, interstitial nephritis, interstitial ?
lung disease, pancreatitis
 Drugs with potential for
serious allergies
• Immediate reactions (anaphylaxis)
β -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 non-allergic?

1. Documentation of acute stage:

• 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

1. Identifying the responsible drug

 Identifying the
1. History
responsible drug
2. Experience with the drug: books indicating specific side effects of drugs
3. Definition of presumed pathomechanism (IgE, T-cell, IgG)
4. Skin tests with non toxic preparations of the drug
– Skin prick test (SPT); Intradermal test (IDT)
– Late reading IDT and patch tests
1. 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
1. Lymphocyte transformation/activation test
2. 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,
γ 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 β -lactams 97-99%
• E.g. β -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 Patient IgE

Widely Used Assay Allergen coupled to

(ImmunoCAP® ImmunoCAP

System) for Conjugate;

Enzyme Anti-IgE

Allergen Specific
IgE Quantification 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
β -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
65-80% 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
β -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

er 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.

er 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.

ud A, et al. Contact Dermatitis, 2001, 45, 321–328

ud 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
• 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)

• 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 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 γ ) 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
β -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 β -
lactam group

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
§

T-cell cross-reactivity extremely rare Mauri-Hellweg D et al J.I. 1996

 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* 50 – 70 % • Colloids (albumin, dextran,
gelatin, hetastarch 1-2%

• Latex 16.7 - 22.3 % • Aprotinin (polypeptide serine

protease inhibitor) 0.5 -
5%
• Antibiotic 10 – 20 %
• Protamine < 0.5%
• Antiseptics (chlorhexidine,
povidone) < 0.5%
• Dyes (patent blue, Isosulfan) and
* Neuromuscular blocking agents like RCM: < 0.5%
suxamthonium, pancuronium, vecuronium,
atracurium, cis-atracurium
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 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

• 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