DRUG (INDUCED) ALLERGY

Fajar Waskito and Hardyanto Soebono

Dept. Dermatology Faculty of Medicine
Gadjah Mada University Yogyakarta
 Pharmacologic
actions Adverse reactions

Theraputic effects Unwanted effects

 Adverse Drug Reactions

Any noxious, unintended, and undesired

effect of a drug that occurs at doses used
in humans for prevention, diagnosis, or
treatment (WHO Definition)
 Adverse Drug Reactions

 106,000 deaths/year in US

 Fifth leading cause of death

 51% of all serious adverse effects reported

after FDA approval

Lazarou J. JAMA 1998;279(15):1200-5

Moore TJ. JAMA 1998;279(19):1571-73
 ADR in Indonesia
Skin
40 Systemic
35 GI
Cardiovascular
30 Urogenital
Respiratory
25
Psychiatric
% 20 Reproduction
Neurologic
15 Ear
10 Liver
Eyes
5 Blood
Metabolic
0
Foetal
ORGAN
Neuromuscular
BPOM, 2000 Endokrin
 Adverse Drug Reactions

 Type A Reactions:
 Common
 Predictable

 Type B Reactions:
 Uncommon
 Not predictable
 Type “A” Adverse Drug Reactions
 Related to known pharmacologic actions
 Usually dose dependent
 Occur in normal patients
 Account for 75-80% of adverse drug
reactions  Over dosage or toxicity:
 Related to total amounts of drugs
 Side Effects:
 Undesirable
 Often unavoidable
 Occur at normal doses
 Secondary or indirect effects:
 Consequences of pharmacologic action (colitis after use of
antibiotics)
 Drug-drug Interactions:
If administered together: Augment or diminish the expected
response
 Type “B” Adverse Drug Reactions
• Usually unrelated to the drug’s
pharmacologic actions
• Generally dose independent
• Often related to patient’s immunologic
responsiveness
Intolerance:
Lowered threshold to normal pharmacologic action of a drug.
Idiosyncratic reactions:
A qualitatively abnormal, unexpected response, differing from it’s pharmacologic
action
Drug allergy
Not predictable, Immune-mediated
Pseudo-allergic (Anaphylactoid)
Not predictable, non immune mediated, direct release mast cell mediators
Pseudoallergic (anaphylactoid) drug-induced ?
Reactions bear a strong clinical resemblance to type I
hypersensitivity, inwitch Mast cell and basophil mediators
(vasoactive amines) have been released, but not through
an Ig-E dependent mechanisms (non immunologic
mechanisms mediated).

Examples :
•“Aspirin allergy” that has high rate of cross-reactivity with
NSAID
•“Radiocontrast allergy” that influenced with hypertonicity
of radiocontrast media
•Morphine
•Certain anaesthetic muscle relaxants
 DRUG ALLERGY
 ADR Type B
 Mild to severe
 Can not be predicted
 No valid nor reliable tests to diagnose
IMMUNOPATHOGENESIS
 Type I Reaction
 Polyvalent protein-
drug complexes
cross-link IgE bound
to mast cells and
basophils leading to
release of preformed
mediators and
synthesis of
leukotrienes
 Type II Reaction
 Drug-specific
antibodies react with
a cell-bound form of
the drug results in
cytotoxicity; or
function as auto-
antibodies, cross-
react with native
proteins results in
complement mediated
lysis
 Type III Reaction
 Circulating immune
complexes consisting
of the drug and
specific antibodies
attach to vascular
walls resulted in
inflammation.
 Type IV Reaction
 Drug bound to TcR
induces cytokine
releases and then
inflammatory
reactions
Classification of drug eruption based on immunological mechanisms

Type Mechanisms Details Manifestations

I Ig E dependent Antigen cross-links Ig E bound to Mast cells Anaphylaxis,
(immediate-type and basophils, release of prefrormed Angioedema,
hypersensitivity) mediators (eg. Histamin) and newly Brochospasm,
mediators (eg. Leukotrienes) urticaria
II Complement Complement activations are via antigen- Lysis,
mediated IgG/IgM? reactions. The antigens are : Cytopenia,
cytotoxicity Drug-modified cell surface antigen Drug purpura
Drug that covalently linked to the Bullous drug
host cell membrane eruptions ?
Systemic drug. Drug and antibody
form immune complexes which
affix to cell membrane
III Immune- Deposition immune complex in the tissue Vasculitis,
complex and elicit immune injury urticaria,
depositions exanthema,
maculopapular.
IV Delayed-type T lymphocytes are sensitized by antigen, contact dermatitis,
hypersensitivity resulting in cytokine release, mononuclear Maculopapular,
cells recruitment, vesicle formations, Exanthema ?
edema
 Risk factors for drug allergy
 Drug related
 High molecular weight (>1000 D).
 Lower molecular weight
Act as haptens
Covalently bind to a carrier protein to cause
immune reaction
 Treatment related
 Dose of drug
 Route of administration
 Risk factors for drug allergy
 Host factors
 Women
 Elderly
 Personal or family history of drug allergy
 Atopic individuals not at more risk but if
reaction occurs it is more severe
 SLE patients
 AIDS patients
 Allergenicity of drugs
Haptenic drugs Complete antigens
Penicillins Insulin
Cephalosporins Enzymes (chymopapain,
asparaginase)
Sulphonamides Foreign antitoxins
Muscle relaxants Organ extracts (ACTH,
hormones)
Anti TBC drugs Vaccines
Anticonvulsant
Thiopental
Quinidine
 Characteristic of Drug Allergy
 Occurs only in small proportion of population
 History of previous drug exposure
 Latent period
 Clinical manifestation are not the same with
pharmacological effects
 Clinical improvement when the drugs stopped
 The symptoms recurrence if exposed to the
same drugs
CLINICAL MANIFESTATIONS
Systemic
 Anaphylaxis  Hematologic

 Serum sickness  Lung

 Drug fever  Liver

 Vasculitis  Kidney
 Neurologic
Dermatologic
Mild
 Makulopapular (morbiliformis)
 Urtikaria
 Contact Allergi
 Photoallergy
 Fixed drug eruption
Severe
 Eritema multiforme
 Stevens Johnson syndrome
 TEN
 Diagnosis
 Medical history (Risk factors, characteristic)
 Clinical Examination (morphology)
 Other investigations: INVESTIGATION

 Skin test EXAMINATION

 Allergen specific IgE

HISTORY
Diagnosis of drug reactions
History :

The length of time between the introduction of

medications and the onset of symptoms

Notes :
Primary immune response generally requires 10-14 days
The rapid onset of symptoms following initial drug
administration suggests an idiosyncratic reaction.
In case of prior sensitization, immune mediated responses
can occur soon

Risk factors for drug reactions

Relationship between type of manifestation and drugs
Skin manifestations of drug eruption
Erythema multiforme
Minor
Major (Steven Johnson Syndrome)
Toxic epidermal necrolysis
Erythema nodusum
Staphylococcal scalded skin syndrome
Erythema multiforme (EM) :
EM is an acute, self limited, often recurrent inflammatory
disorders of the skin and mucous membrane,
characterized by diagnostic iris (Bull’s eye, target lesion)
and well defined histopathology findings.

It is divided into :
EM minor
EM major (Steven-Johnson Syndrome) : EM minor with
systemic involvement and more severe

Pathophysiologic
Vascular & tissue damage is a result of a type III
hypersensitivity or type II with blood vessel serving as
hapten
Etiology
The underlying infections (most are in EM minor)
Virus (HSV, Mycoplasma pneumoniae and vaccines)
Fungi
Bacteria
Parasites
The drug (eg. Penicillin, barbiturate, phenytoin,
sulfonamides and phenolphthalein)
Food additives and dyes
Contactant
Physical factors (cold, sun, X-rays)
Collagen vascular diseases
Malignancy
Pregnancy
Clinical manifestations :
Sudden onset of a symmetrical distribution especially
iris lesions
Predilections : mucous membrane, palms, soles, dorsal
surface of the hands, extensor surfaces of forearms
and legs. The most characteristic lesions are iris
lesions and mucous membrane involvement with thick
hemorrhagic crust on lips. Prodromal symptoms are
burn or itch sometimes with systemic signs.
Nikolsky sign +
Histopathology :
Epidermis : necrotic keratinocytes, spongiosis, edema
intracell
Dermo-epidermal interface : Endothelial vascular
swelling
Dermis : edema, extravasated erythrocytes,
perivascular lymphohistiocytes infiltrate
Laboratory examinations :
Immunofluorescence to differentiate with other subepidermal
blistering diseases.

Treatment :
Mild cases :
Elimination of suspected etiologic factors
Discontinue non essential drugs
Symptomatic and supportive treatment
Treat the underlying infections
Give attention to oral hygiene and ocular care

More severe cases

Fluid and electrolyte balance
Corticosteroid can be given to severe cases
Toxic epidermal necrolysis
(Lyell’s Disease, Non-Staphylococcal Scalded Skin Syndrome)

Pathophysiologic & Histopathologic features are

indistinguishable with severe EM.

Etiology :
Drugs (eg. Sulfonamide, pyrazolones, barbiturates,
antibiotics)
Poisoning CO
Lymphoma
Measles, Smallpox vaccination
Radiotherapy
Graft versus Host reactions
Idiopathic
Treatments :
Exclude S4. If it’s uncertain, sytemic antibiotics can be
given
In general, the treatments are almost the same with EM
Giving corticosteroids are in contradictive, except in severe
cases
Erythema nodusum (EN)
EN is reactive erythema characterized by inflammatory
non ulcerating nodules that are usually tender, multiple,
bilateral (usually resolves in 3 – 6 weeks without scarring)

Predilections : Extensor aspects of the lower legs

Etiology & pathogenesis

Drugs :
Estrogen, oral contraseptives
Aminopyrines, phenacetin etc.

Infections :
Bacterial (eg. Streptococcus, Mycobacterioses etc.)
Chlamydial
Fungal :
Protozoan
Viral
Malignancy
Miscellanous
Clinical manifestations :
The peak incidence is in the young adulthood
Women 9 x more often than men
Prodrome : Fever, malaise, arthralgia
Sudden onset of multiple, tender, red, warm, bilateral
nodules and diameter 1 – 15 cm.
Predilections : Shins, arms, face, calves and trunk
The bruise-like evolution is pathognomonic

Histopathology :
Septal panniculutis, and later evolve granulomatous and
fibrotic.

Laboratory :
CBC, ESR, ASTO, throat culture (Streptococcus)
Chest X-ray, intradermal test for TBC, Coccidioidomycosis,
blastomycosis and histoplasmosis
Treatment :
Treat the underlying cause
Symptomatic treatment
Total Bedrest
NSAID
Potassium Iodides
Corticosteroid can be used for :
1. Sarcoidosis, if it is causative factors
2. Severe resistant idiopathic with no demonstrable
associated infections
3. Few refractory and/or recurrent lesions
(intralesional corticosteroid)
Staphylococcal scalded skin syndrome (S4)
S4 is caused by an exfoliative toxin, especially produced
by Staphylococcus aureus of group II, phage type 71 even
in remote sites.

Pathogenesis :
The toxin causes a rent within the epidermis (below the
stratum granulosum)
Antibodies will neutralize toxin, and causing spontaneous
resolution and protecting the patients from further attack.

Predisposition : children

Cinical manifestations :
Clinical pictures have close resemblance with TEN, but
have course + 10 days. Lightly erythematous skin, the
upper layer of epidermis peel off
Therapy : Macrolide antibiotics
Clinical manifestations :
Prodrome : erythema, anorexia, malaise, low grade
fever
Follow by sheets of epidermis peel off (Scalded skin)
Large flaccid bullae
The Nikolsky sign is positive
The desquamative phase is the final stage

Laboratory
Nikolsky sign (TEN = positive, S4 = negative)
Tzanck smear (inflammatory cells, round or cuboid
epithelial cells with large nuclei = TEN and are not for
S4)
Lacks the vacuolar alteration and epidermis necrosis
seen in PA of TSS
The methodology of skin testing :
Skin testing begin with prick testing
If the result was negative, intradermal testing was
performed
Skin testing should include positive (histamine) and
negative (saline).
A positive response is characterized by wheal & flare

False negative sometimes find in patients in :

Critically ill
Hypotensive
Receive H1 antihistamines

The result only provide information about the

current state
2. RAST (Radioallergosorbent test)
Allergen binds to IgE of suspected patients, and is then
detected by antibody that is specific for IgE. This
antibody is conjugated with radioisotope, and the
degree of IgE binding is determined using appropriate
detection system

3. Patch test is a miniature of allergic contact dermatitis so

it’s look like provocation test with standardized allergens

4.Tuberculin type testing

5.Lymphocyte proliferation test is used to know the

specific antigen, inwitch antigen antibody complex are
exposed to lymphocytes. If the patients are sensitive,
lymphocytes will proliferate in significant amount.
6. Cytokine induction test is almost similar with
lymphocyte proliferation test

The result of all tests often correlate better

with recent drug exposure

7. Provocation test is useful when the likelihood of a

true allergy is low. Drug administered initially with low
doses which serially increased until full dose therapy is
reached

The time interval between rising doses :

In type I hypersensitivity : 20 – 30 minutes
In type IV hypersensitivity : 24 – 48 hours
MANAGEMENT

 Drug treatment
 Allergen avoidance
 Desensitization
 Desensitization
 Sometime are effective
 Necessary if certain medication cannot be
given
 Some protocols have been available
(Penicillin, Sulfonamide, Insulin)
 Risky in serious drug allergy (anaphylaxis,
TEN etc)
 Prepare intensive care and rescue drugs
(epinephrin, oxygen etc)
Mechanism of Desensitization

Low dose antigen

Higher threshold to mediator release

Tolerance
 Indications, drugs, and diseases treated with rapid
desensitisasion

Indication Drug most frequently used Disease

Anaphylactic Antibiotics Sepsis, Meningitis,
Beta-lactams Pneumonia, Pyelonephritis
Fluoroquinolones
Chemotherapy
Cancers (breast, colon,
Platins ovarians)
Monocalonal abs
Rituximab, Trastuzumab Chronic inflammatory dis.
Cancers
Anaphylactoid Aspirin/NSAIDs Cardiac protection,
asthma, Chron’s diseases

Vancomycin
MRSA

Chemotherapy drugs Cancers (breast, colon,

Taxenes ovarians)
Adkinson and Prograsic,2001
 Desensitization to aspirin in patient with
urticaria/angioedema
Time (min) Dose (mg)

0 0,1
20 0,3
40 1
60 3
80 10
100 30
120 40
140 81
160 162
Adapted from Castells (2006).
 PREVENTION

 Use drugs as necessary

 Remember and record all the drugs
which might have induced allergy
 Avoid the suspected drugs