DRUG ERUPTION

Hildebrand Hanoch Victor

Dept. Ilmu Penyakit Dalam
FK UKI
2015
 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

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

Perforin/ CXCL-8.
Immune IFN, TNF IL-5, IL-4/IL-13
IgE IgG IgG GranzymeB GM-CSF, IL-17 (?)
reactant (TH1 cells) (TH2 cells)
(CTL) (T-cells)

Antigen presented by Antigen presented by Cell-associated antigen Antigen presented by

Cell- or matrix-
Antigen Soluble antigen Soluble antigen cells or direct T cell cells or direct T cell or direct T cell cells or direct T cell
associated antigen
stimulation stimulation stimulation stimulation

Effector FcR+ cells

FcR+ cells Macrophage
Mast-cell activation (phagocytes, NK Eosinophils T cells Neutrophils
Complement activation
cells)
immune complex
blood
vessel
TH2
platelets IFN-
TH1
Ag
IL-4
CXCL8 PMN
IL-5 eotaxin
CTL GM-CSF

cytokines, inflammatory
chemokines, cytokines, cytokines, inflammatory
mediators
cytotoxins mediators

Chronic asthma,
Contact dermatitis,
Example of Tuberculin reaction, chronic allergic
Allergic rhinitis, asthma, Some drug allergies Serum sickness, maculopapular and AGEP,
hypersen-sitivity contact dermatitis rhinitis, maculo-
systemic anaphylaxis (e.g., penicillin) Arthus reaction bullous exanthema, Behet disease
reaction (with IVc) papular exanthema
hepatitis
with 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)
 Drug Eruptions
DRESS Sydrome
Urticaria
Angioedema/anaphylaxis
Drug-induced exanthems
Hypersensitivity vasculitis
Exfoliative dermatitis/Erythroderma
SJS/TEN
Fixed drug eruption
Photosensitivity
 DRESS Syndrome
Drug Rash with Eosinophilia and Systemic Symptoms
Formerly called Hypersensitivity Syndrome (HSS)
Typically presents with rash and fever (87%), classically erythematous
follicular papules and pustules, but may also include bullae or purpura.
Other severe systemic manifestations such as hepatitis (51%), arthralgias,
lymphadenopathy (75%), interstitial nephritis (11%), or hematologic
abnormalities (30%).
Hematologic abnormalities include eosinophilia, thrombocytopenia,
neutropenia, and atypical lymphocytosis.
Other symptoms: pruritis, nephritis, oliguria, hepato-renal syndrome,
athralgia, and asthenia.
Can affect any organ system (lungs, CNS, GI, etc.)
DDx includes SJS/TEN, hypereosinophilic syndrome, and Stills disease.
Skin biopsy is non-specific.
 DRESS Syndrome
Common causes: aromatic anticonvulsants (oxcarbazepine,
carbamazepine, phenytoin, phenobarbital, etc.) and sulfonamides.
Other drugs implicated:
lamotrigine
allopurinol
NSAIDs
captopril
CCBs
mexiletine
fluoxetine
dapsone
metronidazole
minocycline
antiretrovirals.
 DRESS Syndrome
Overall risk for phenytoin is between 0.1-0.01%.
Usually occurs 2-6 weeks after initiation of the medication, which is later
than most drug eruptions. May be difficult to distinguish from serum
sickness and vasculitis.
Median onset of DRESS syndrome after initiation of therapy with
Trileptal is 13 days (range 4-60).
No definite evidence of cross-reactivity with other agents, but it is a
possibility.
Treatment is supportive.
Medication should be stopped as soon as the diagnosis is suspected.
Severity is dependent upon the amount of time the drug is continued
after hypersensitivity occurs.
Corticosteroids have been required in some cases, but their use is
controversial.
 Urticaria
Time to onset: immediate, accelerated (hours), or delayed
(days).
Type I hypersensitivity reactions: antibiotics (especially PCN,
cephalosporins, and sulfonamides), local anesthetics,
radiocontrast media, blood products, and gamma globulin.
Non-immune urticaria: radiocontrast media and long-acting
ACE-inhibitors (due to changes in vascular response to
bradykinin).
Mast cell degranulation by non-IgE mechanisms: opiate
analgesics, anesthetic muscle relaxants, and Vancomycin (Red
Man Syndrome, which can be worsened by concommitant
opiate use).
 Angioedema/Anaphylaxis
Caused by degranulation of mast cells in the deeper dermis and
subcutaneous tissues.
May occur along with urticaria (50% of cases)
Can be life-threatening if it causes laryngeal edema or tongue
swelling.
Can be non-mast cell mediated, as in the case of ACE-inhibitors.
 Drug-induced Exanthems
Account for close to 75% of all drug eruptions.
Morbilliform, maculopapular eruptions.
Most commonly implicated medications are the most commonly prescribed
medications (antibiotics, sulfa).
Usually begin in dependent areas and generalize.
Often associated with pruritis, low-grade fever, eosinophilia.
May be the early stage of more severe reactions such as toxic epidermal necrolysis,
DRESS, or serum sickness
Onset within 2 weeks of starting a new drug, or within days of re-exposure.
Delayed (type IV) hypersensitivity is most likely etiology.
More common in patients with altered immunity, such as those with HIV or
mononucleosis (ampicillin rash).
Treatment is dicontinuation of the drug. Antihistamines, topical steroids, and topical
antipruritics may also help.
 Hypersensitivity vasculitis
American College of Rheumatology proposed the following five criteria. The
presence of three or more had a sensitivity of 71% and a specificity of 84%
for the diagnosis
Age > 16
Use of possible offending drug in temporal relation to symptoms
Palpable purpura
Maculopapular rash
Biopsy of a skin lesion showing neutrophils around an arteriole or venule.
Most likely due to drugs that can act as haptens to stimulate the immune
response: PCN, cephalosporins, sulfonamides, phenytoin, and allopurinol.
Additional findings: fever, urticaria, arthralgias, LAD, low complement levels,
and elevated ESR.
 Exfoliative dermatitis/
Erythroderma
Erythroderma is defined as a cutaneous reactional state with
chronic erythema and scale involving greater than 50% of the
body surface area. It can result from drugs, atopic dermatitis,
psoriasis, and malignancies such as cutaneous T-cell lymphoma.
Drugs, including gold, arsenic, mercury, PCN, and barbituates,
are implicated in about 10% of cases.
Usually begins as an eczematous or morbilliform eruption and
progresses.
 SJS/TEN
Stevens-Johnson Syndrome and toxic epidermal necrolysis are likely two
manifestations on the same spectrum. The disease is best termed SJS when
epidermal detachment involves less than 10% of the body surface area,
whereas TEN involves greater than 30%.
SJS is distinct from erythema multiforme major, which is usually caused by
infections and runs a benign course. SJS is usually drug induced and can be
fatal.
SJS and TEN usually occur 1-3 weeks after exposure, but can occur more
rapidly with re-exposure, which suggests an immunologic mechanism.
Mucosal involvement is seen in 90% of cases, including painful crusts and
erosions on the oral mucosa, conjuntivae, and genital mucosa.
 SJS/TEN
Frozen section of the denuded epidermis will reveal full-
thickness epidermal necrosis.
Differential includes exfoliative erythroderma, paraneoplastic
pemphigus, acute exanthematous pustulosis, and staph scalded
skin syndrome, but none of these disorders displays full-
thickness epidermal necrosis.
Patients are best managed as burn victims.
Corticosteroids are not recommended.
 Fixed Drug Eruptions
Drug eruption that occurs at the same location every time a
particular medication is used.
Begins as an erythematous, edematous plaque with a grayish
center or frank bullae, then progresses to dark, post-
inflammatory pigmentation.
Sites include the mouth, genetalia, face, and acral areas.
Causes include phenolphthalein, tetracyclines, barbituates,
sulfonamides, NSAIDs, and salicylates.
 Photosensitivity
Two types include phototoxic eruptions and photoallergic eruptions.
Phototoxic eruptions are due to absorption of UV light (usually UVA) by the
drug, which causes a release of energy and damage to cells. Looks like a bad
sunburn, which may blister.
Photoallergic eruptions are a lymphocyte-mediated reaction caused by
exposure to UVA, which converts the drug to an immunologically active
compound that activates lymphocytes, causing an eczematous reaction in a
photodistribution.
Usually due to topical agents including fragrances and biocides in soaps.
Both types can be caused by phenothiazines, chlorpromazine, sulfa, and
NSAIDS, although phototoxic reactions are more common with these agents.
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
Immediate type: 16
14

silent sensitization, 12

10
well tolerated; 8
at re-exposure quick 6
4
development of symptoms 2
(urticaria, anaphylaxis) 0

1
2
3
4
5

8
9
0
1
2
3
4
5
6
7
8
12
12
13
13
13
13
13
13
13
13
13
45
40
35
() ()
Delayed type:
30
Sensitization and symptoms often 25
at 8th 10th day of therapy 20
15
(exanthema) 10
5
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
 Allergic vs non-allergic
drug hypersensitivity
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)
Non-allergic
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:
MC
penicillin/cephalosporin, pyrazolones*
quinolones*, (recombinant) proteins hapten-
carrier

Non-immune hypersensitivty reaction with:

NSAID (acetylsalicylic acid, diclofenac*, .)
radio contrast media*, muscle relaxants*,
gelatine-infusions*
Histamine, LT, TNFa,
* Both IgE and non-immune mediated mechanisms Tryptase,....
possible
 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

Maculopapular exanthem
(MPE) Acute generalized
Bullous
Exanthem exanthematous
pustulosis (AGEP)
 Acute Generalized Exanthematous
Pustulosis (AGEP)

Clinical manifestations
Generalized, sterile pustules
Fever (>38C)
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 systemic

symptoms (often hepatitis, sometimes pancreatitis, interstitial 10 %
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)
-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

2. Identifying the responsible drug

 Identifying the responsible drug
1. History
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
5. 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
6. Lymphocyte transformation/activation test
7. 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
Delayed reactions
Immediate reactions Complete blood count:
eosinophilia and lymphocytosis,
Serum tryptase leukocytosis
Serum histamine 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)
 Delayed reactions
Patch tests
Drug patch tests are positive in 3250% 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, 321328
Barbaud A. Toxicology 2005; 209:209216
 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
 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
 Prevention

Patient Education
Potentially cross-reacting
drugs
Medic Alert cards/bracelets
Pharmacovigilance
Notify local drug regulatory
agencies
Electronic Medical Records
 Thank You

El Kabron, 2015
 GLORIA MODULE 11:
Drug Allergy (Part 2)
Clinical Management of Drug
Allergy

Authors
Werner Pichler, Switzerland
Bernard Thong, Singapore