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Chapter
10 Drug-Induced Skin Reactions and GVHD

Skin and mucocutaneous lesions induced by a drug or by its metabolites are called drug eruptions. Some cuta-
neous drug reactions present a specific morphological pattern. However, most drug eruptions can present the
appearance of any cutaneous lesion. It is necessary for dermatologists to take a detailed patients history of
medication use as well as a medical history. It is clinically important to differentiate drug-induced skin reactions
from viral rash and graft-versus-host disease (GVHD); this differentiation is sometimes difficult.

A. Drug-induced skin reactions

10
Outline
Drug-induced skin reaction or drug eruption is a general
term for eruptions in the skin and mucosa induced by a
drug or its metabolites.
Drug-induced skin reactions show various morphologies.

Clinical images are available in hardcopy only.

General information
Maculopapular or morbilliform eruptions may be the most com-
mon of all cutaneous drug reactions. It is also known that cuta-
neous drug reactions present the specific morphological patterns.
(Figs. 10.1-1 and 10.1-2). In diagnosing skin diseases, it is essen-
tial to consider drugs as a possible cause of any eruption, because
drug eruptions can take the form of any skin lesion. Drug eruptions
may be accompanied by general symptoms including fatigue,
a b c d e f g h
fever, i
lymph j
node k l disfunction
enlargement, m nof the internal
o porgansq r
such as liver, kidneys or bone marrow, hypotension and shock.

Classification, Pathogenesis
Drug eruptions are roughly divided into immunologic and non-
immunologic. The pathogenesis is unclear in some cases. The
eruptions are often classified by their clinical features (Table
10.1, Figs. 10.2-1 and 10.2-2).
Clinical images are available in hardcopy only.
Treatment
It is essential to discontinue the causative medication. In seri-
ous cases, such as anaphylactic shock, systemic management
using steroids in large doses including antihistamines, epineph-
rines, and steroids in large doses, including by pulse therapy.

a b c d e f g h i a. Classification
j k l ofmdrugn eruptions
o p by q r
Fig. 10.1-1 Drug-induced skin reaction. pathogenesis (Table 10.2)
a: Diffuse edematous erythema on the back. Each
eruption is an erythema multiforme-like erythe-
ma of 1 cm to 2 cm in diameter that gradually 1. Immunologic drug reactions
enlarged and tended to coalesce. b: Edematous
itchy erythema coalesced into a large plaque. A drug or the complex of a drug and a serum protein becomes

126
 A. Drug-induced skin reactions 127

Table 10.1 Drug-induced skin reactions and their typical causative drugs.
Type of eruption in drug-
Causative drugs
induced reactions
Maculopapular Iohexol, iomeprol, ampicillin, amoxicillin, carbamazepine, mexiletine, tiopronin
Photosensitive Sparfloxacin, fleroxacin, lomefloxacin , piroxicam, ampiroxicam, griseofulvin, mequitazine, ketoprofen
Fixed-drug eruption Allylisopropylacetyl urea, mefenamic acid, ethenzamide, barbital, minocycline,
sulfamethoxazole, piroxicam, fluorouracil
Erythema multiforme Iohexol, carbamazepine, amoxicillin, tiopronin, phenytoin, diltiazem, mexiletine
Lichenoid Tiopronin, captopril, interferon a, cyanamide, oxatomide
Urticarial Cefaclor, minocycline, iohexol, aspirin, cetraxate, mefenamic acid
Toxic epidermal necrolysis Cefzonam, penicillin, phenobarbital, chlormezanone, carbamazepine, methazolamide, acetaminophen,
(TEN) allopurinol, diclofenac
Stevens-Johnson syndrome Penicillin, chlorpromazine, sulfamethoxazole, sodium aurothiomalate, phenytoin
Erythrodermic Carbamazepine, sodium aurothiomalate, cyanamide, allopurinol, ampicillin
Vesiculo-bullous D-penicillamine, tiopronin, captopril, bucillamine, alacepril
10
Eczematous Penicillin, chlorpromazine, chlorthiazide, promethazine
Purpuric Sodium aurothiomalate, sulfamethoxazole, penicillin, aspirin

antigenic, causing a drug eruption that results from immunologi-

cal processes. That is, a drug eruption occurs in specific individu-
als whose antibodies and lymphocytes react against specific
antigens. Although type I, II, III, and IV hypersensitivities are
thought to cause drug eruptions (Coombs and Gell classification),
the details of the pathogeneses are unknown.
IgE mediated type I allergy: Within 2 hours after exposure to
an antigen (e.g., penicillin or some NSAIDs), urticaria or anaphy-
lactic shock occurs. Clinical images are available
Type II allergy: Complements are activated by an antigenic drug in hardcopy only.

that connects with tissues, resulting in hemolytic anemia and

thrombocytopenia. It is observed in some cases of purpura-like
eruptions.
Immune complex-associated type III allergy: Immune com-
plex deposits in tissues, causing disorders. Vasculitic eruptions
are thought to be caused by this mechanism.
Type IV allergy: A delayed hypersensitivity reaction is induced
g j
by T cells that have been sensitized to drug antigens. It isa knownb c d e f h i
that many types of drug eruptions, such eczema-like eruptions,
are produced by type IV allergy or by T-cell mechanisms that
resemble type IV allergy.

Clinical images are available

in hardcopy only.
2. Non-immunologic drug-induced skin
reactions
Drug-induced skin reactions without an immunologic patho-
genesis may affect anyone, regardless of whetherathere has
b beenc d e f g h i j k
sensitization.The pathogenesis of drug-induced skin reactions can Fig. 10.1-2 Drug-induced skin reaction.
also be classified pharmacokinetically. c: Drug-induced erythema enlarged and coa-
Pharmacologic effects: Drug-induced skin reactions may be pro- lesced to form erythroderma. d: Drug eruption
caused by tegafur.
duced by essential pharmacological action of the drug. Hair loss
 128 10 Drug-Induced Skin Reactions and GVHD

Table 10.2 Drug-induced skin reactions classified by mechanism.

Immunologic
Type I hypersensitivity (via IgE antibodies; acute onset within 2 hours
after drug intake)
Type II hypersensitivity (eruption caused by thrombocytopenia and
hemolysis resulting from complement activation)
Type III hypersensitivity (immunocomplex deposition in skin components)
Clinical images are available Type IV hypersensitivity (reactions caused by activated T cells)
in hardcopy only.
Non-immunologic
Pharmacological effects
Accumulation
Drug interaction
Patient-specific conditions

a b c d e f g h i j k l m n o p q r
caused by anticancer agents and exfoliation in palms and soles
10 caused by retinoids are examples.
Accumulation: A drug accumulates in the skin or mucous mem-
branes from prolonged use (arsenic melanoderma and argyria are
Clinical images are available examples of accumulation disorders).
in hardcopy only. Drug interaction: One drug may inhibit another drugs metabo-
lism or excretion, or it may influence protein binding, leading to
the same symptoms as those in drug overdose.
Specific condition of patients: Inherited enzyme deficiency may
a b c d e f g h i
cause j
drug k
reactions; l m reaction
excessive n o
occurs p
against a qminuter
amount of drug (intolerance). An unexpected action of the drug is
caused (idiosyncrasy).

b. Classification of drug eruptions by

Clinical images are available
in hardcopy only.
characteristic skin features
Although maculopapular eruption (multiple edematous ery-
thema on the extremities and trunk) are the most common;
drug-induced skin reactions can appear as any kind of cuta-
neous lesion (Table 10.1). When seeing patients with any
types of eruption, dermatologists should always carefully con-
sider the possibility of precedent drug reactions.

c. Methods of identifying the causative

drug
History is taken on drug-induced skin reactions and on exacer-
g p
b c d e f h i j
bation k remission
or l ofmeruptions
n influenced
o by useqor discontinu-
r
Fig. 10.2-1 Various types of drug-induced ation of a drug. If the eruption is suspected to be drug-induced
skin reaction.
a, b: Erythema multiforme-like. Although uni-
reactions, tests listed below are conducted for identification
formly colored erythematous plaques are mainly (Chapter 5).
seen, newly formed erythema is seen at the Skin test (scratch test, prick test, intradermal test)
periphery, some parts of which show the target- Patch test
like appearance that characterizes erythema mul-
tiforme. c: Purpuric. Dark red macules up to 1 Drug lymphocyte stimulation test (DLST)
cm in diameter are observed. These do not disap- Rechallenge test (absolutely contrainidicated in severe forms
pear by diascopy pressure, which indicates that of drug reactions)
the eruption is purpura.
 A. Drug-induced skin reactions 129

d. Specific types of drug-induced skin

reactions

1. Fixed drug eruption (FDE)

Definition
Fixed drug eruptions (FDEs) are eruptions that recur at the
same site each time the same drug is administered. They fre- Clinical images are available in hardcopy only.
quently occur at mucocutaneous junctions.

Clinical features
FDEs frequently occur at mucocutaneous junctions, such as in
the perioral area, lips and genitalia, and in the extremities. They
are characterized by a single or a few sharply demarcated red or 10
purple patches (Fig. 10.3), with a diameter of 1 cm to 10 cm.
Multiple patches may also occur. They may appear as blistering
or erosion. Itching and pain are common. The lesions appear sev-
eral minutes to several hours after the administration
a b of thec d e f g h i j k
causative drug. They heal in 2 to 5 weeks, leaving pigmentation.
If the same drug was administered repeatedly, the dark brown
pigmentation intensifies from inflammation in the basal layer,
and subsequent melanin deposition in the dermis (post-imflam-
matory pigmentation).

Pathogenesis
FDEs are caused by the activation of cytotoxic T lymphocytes
in the basal layer by drugs. Common causative drugs are
NSAIDs, tetracyclines, sulfa drugs, phenacetin, hypnogenics and Clinical images are available in hardcopy only.
food additives.

Diagnosis
FDEs are diagnosed by detailed history-taking on drugs and
the course of the eruptions. A patch test performed on the site
where an eruption has occurred is positive with high frequency; it
is diagnostically meaningful.

Treatment
a b c d
The causative drug should be discontinued.
2. Adverse drug reactions in skin that can
result in death
There are several specific clinical types of drug-induced skin
reactions that may lead to death. Toxic epidermal necrolysis
(TEN) has the highest mortality (30-35%); Stevens-Johnson syn-
drome and transitional forms correspond to the same syndrome,
but with less extensive skin detachment and a lower mortality (5-
15%).
Hypersensitivity syndrome, sometimes called drug-induced
e f g h i j k l
Fig. 10.2-2 Various types of drug eruption.
d, e: Urticarial drug eruptions. Edematous erythe-
ma resembling urticaria is seen on the trunk and
palms.
Generalized bullous MEMO
fixed drug eruption
Blistering may be present in some fixed drug
eruptions, and it may spread on the whole
body surface, becoming severe. Generalized
bullous fixed drug eruption may be catego-
rized with toxic epidermal necrolysis (TEN),
which is described in the following section.
 130 10 Drug-Induced Skin Reactions and GVHD

Clinical images are available

Clinical images are available in hardcopy only.
in hardcopy only.

a b c d a e b f c g d h e i f j g k h l i m j n k o l p m q n r o
Clinical images are available in hardcopy
only.

10 Clinical images are available

Clinical images are available in hardcopy only.
in hardcopy only.

b c d ae bf cg dh ei af j gk
b h
cl dim ejn kfo glp hq
m ni r oj p
k
Fig. 10.3 Fixed drug eruption (FDE).
a: Early FDE on the right eyelid. Early lesions are edematous erythema without pigmentation. b:
FDE on the abdomen. Repeated intake of the causative drug results in a severely pigmented FDE
lesion. c, d: FDE on the thigh. The center of the lesion shows characteristic pigmentation caused
by chronic inflammation. The periphery is erythematous, which suggests recent intake of the
causative drug. e: FDE on the interdigital area. Erythema and bullous lesions are seen.

hypersensitivity syndrome (DIHS) or drug reaction with

eosinophilia and systemic symptoms (DRESS), has a mortality of
about 10% or less.

Clinical images are available in hardcopy only.

1) Toxic epidermal necrolysis (TEN)
Synonym: Lyells syndrome

Clinical features, Classification

Clinical images are available in hardcopy only.
Fig. 10.4-1 Toxic epidermal necrolysis (TEN).
Toxic epidermal necrolysis (TEN) is one of the severest drug
eruptions. It is accompanied by fever, and erythema and blister-
ing on the whole body surface. It leads to marked epidermal
necrosis and exfoliation (Figs. 10.4-1 and 10.4-2). It is closely
related to Stevens-Johnson syndrome (SJS) (Fig. 10.5). TEN is
classified into several types according to the clinical course.
TEN developing from SJS: Most cases of TEN develop from
SJS. Vaguely outlined, small, dark red edematous erythema
sparsely appear on the whole body and gradually spread. They
subsequently increase and form blisters and erosion. Typical pri-
mary lesions are characterized by so-called target lesions with
dusky centers. Severe erosion develops in the oral mucosa, and
systemic symptoms such as fever and fatigue are seen. SJS is
characterized by the transformation of erythema into blistering
 A. Drug-induced skin reactions 131

fixed drug
generalized TEN SJS EM
eruption
FDE
(FDE)
Clinical images are available in hardcopy only.

Fig. 10.5 The pathogenic association of fixed drug eruption (FDE),

toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome
(SJS) and erythema multiforme (EM).

and erosion with dark red patches at the periphery (Chapter 9). Fig. 10.4-2 Toxic epidermal necrolysis (TEN).
Rapid extensive type: This is the type that Lyell first reported.
Two to 3 days after intake of the causative drug, erythroderma
and extensive erosions occur on the whole body surface without
preceding macules, and the skin exfoliates easily; it is similar to a 10
large burn (second-degree). This type accounts for several per-
cent of all TEN cases (Fig. 10.6).

Pathogenesis
It is widely accepted that the cellular functions of cytotoxic T
cells are abnormally enhanced by certain drugs, including sulfa
drugs, penicillin, barbituric acids, aspirins, pyrazolone drugs, and
anticonvulsants, and epidermal necrosis and subepidermal sepa- Clinical images are available in hardcopy only.
ration occurs as a result. Fas-Fas ligands, which induce apoptosis
in epidermal cells, are thought be involved in the occurrence of
TEN.

Treatment
Use of the causative drug should be discontinued immediately.
Systemic glucocorticosteroids in high doses, including pulse ther-
apy, are widely known to be useful in the early stages of TEN, but
not in the late stage of the disease course. Intensive care with top-
a b c d e f g h
ical treatment and body fluid management similar to the patients
with burns are essential. Plasma exchange may be conducted, and
large doses of immunoglobulins may also be applied. The causative
drug must not be readministered.

2) Drug-induced hypersensitivity syndrome Clinical images are available in hardcopy only.

Synonyms: Drug hypersensitivity syndrome, Drug reaction

with eosinophilia and systemic symptoms (DRESS)

There is still controversy on the naming of this newly proposed

g
concept of the disease condition, but each different disease namea b c d e f h i
may indicate the same or similar condition which is induced by Fig. 10.6 Diffuse erythematous toxic epider-
mal necrolysis (Lyell's syndrome).
drug. Drug-induced hypersensitivity syndrome (DIHS) is proposed a: The causative drugs here are antituberculosis
by a group of Japanese dermatologists which holds that skin lesions drugs, which were used for tuberculosis associat-
are caused by a combination of drug allergy and reactivated latent ed with AIDS. Generalized shedding of the epi-
dermis on the whole body is seen. The dermis is
viral infection, specifically human herpes virus 6 (HHV 6) infec- pink where the skin exfoliates. b: Severe erosions
tion. Two to 6 weeks after administration of a specific drug, fever and ulcers in the oral region.
 132 10 Drug-Induced Skin Reactions and GVHD
Clinical images are available in hardcopy only.
10
Clinical images are available in hardcopy only.
Fig. 10.7 Drug-induced hypersensitivity
syndrome (DIHS).
B. GVHD and viral eruptions
Table 10.3 Diagnostic criteria for drug-induced hypersensitivity
syndrome (DIHS).
1. Maculopapular rash develops more than 3 weeks after starting a certain
drugs.
2. Lymphadenopathy
3. Fever (>38C)
4. Leukocytosis (>10 109/L)
a. Atypical lymphocytosis
b. Eosinophilia
5. Hepatitis (ALT >100 U/L)
6. HHV-6 reactivation
The diagnosis is confirmed by the presence of five of the six criteria above.
(Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS):
a reaction induced by a complex interplay among herpes viruses and antivi-
ral and antidrug immune responses. Allergology International 2006; 55: 1-8).
and generalized maculopapular erythema occurs (Fig. 10.7), which
results in erythroderma in some cases. Enlargement of superficial
lymph nodes, liver dysfunction and hematological abnormalities
(leukocytosis, appearance of atypical lymphocytes, increase of
eosinophils) occur. There is also a report that suggests the
involvement of cytomegalovirus and human herpes virus (HHV-
7) in DIHS. The diagnostic criteria are listed in Table 10.3 (also
refer to Chapter 23 for viral infections).
Drug reaction with eosinophilia and systemic symptoms
(DRESS) is thought to be the same or similar syndrome, which is
mainly used by European dermatologists group. The important
point is that dermatologists should be aware of these systemic
drug-induced reactions in association with marked eruption, and
that routine laboratory examination is necessary when a drug
eruption is suspected.
The treatements include systemic corticosteroid and termina-
tion of the causative drug.
1. Graft-versus-host disease (GVHD)
Outline
After bone marrow transplantation, other organ trans-
plantation or transfusion, donor lymphocytes are stimu-
lated by major and/or minor histocompatibility locus
antigens and subsequently target host tissues for cyto-
toxic damage.
The skin, intestinal tract and liver are the main affected
organs.
In acute GVHD, erythematous macules occurs on the
palms and spread over the whole body. In chronic GVHD,
lichen-planus-like and scleroderma-like eruptions are
found.
 B. GVHD and viral eruptions 133

Definition, Pathogenesis
When donor-derived blood cells circulate in the patients skin
after transplantation, the immunocompetent donor, T cells, may
recognize the foreign hosts histocompatibility locus antigens
(HLA). Subsequently, an immune reaction against the hosts
organs occurs. It may also be caused by general blood transfusions.

Classification
Clinical images are available in hardcopy only.
As shown in Table 10.4, graft-versus-host disease (GVHD) is
categorized by the onset. The skin, digestive tract and liver are
the main organs affected, and the symptoms are mainly seen in
those organs. Post-transfusion GVHD occurs about 10 days after
a transfusion and has a poor prognosis. Congenital GVHD occurs a b c d e f g h
after birth, and intractable dermatitis, diarrhea, opportunistic
infections, and disturbance in growth are caused by lymphocytes
transferred from the mother. 10
Clinical features
Acute GVHD: In most cases, 10 to 30 days after a graft, edema-
tous erythema appears on the extremities and trunk. It may be
accompanied by slight itching. In severe cases, the eruptions coa-
lesce and may develop into erythroderma, blistering or erosion
(Figs. 10.8-1 and 10.8-2). Symptoms of acute GVHD may Clinical images are available in hardcopy only.
remain longer even after the first 100 days or more after trans-
plantation, as a result of recent improvements in immunosuppres-
sive drugs.
Chronic GVHD: This includes lichenoid forms and scleroder-
moid forms. The lichenoid forms multiple purplish-red plaques
resembling lichen planus, and the sclerodermoid forms sclerotic
lesions resembling scleroderma.
The severity of GVHD is classified according to the severity
of the skin lesions and other organ disorders (Table 10.5). g
a b c d e f h i
Pathology
GVHD pathologically presents a lichenoid reaction. Intrader-
mal lymphocyte infiltration, necrosis of the epidermal cells, and

Table 10.4 Classification of graft-versus-host disease (GVHD). Clinical images are available in hardcopy only.
Duration after
Type of
transplantation/ Symptoms
GVHD
transfusion
Hyperacute 7 to 14 days Fever, diarrhea, erythrodermic skin erup-
tion, pulmonary edema, heart failure
a b c d e f g h i j
Acute Up to 100 days Triad (fever, diarrhea and liver dysfunction).
Poorly demarcated erythema seen on the Fig. 10.8-1 Acute graft-versus-host disease
face and palmoplantar area. In severe (GVHD).
cases, TEN and erythroderma. a: Diffuse erythema on the back after bone mar-
Chronic More than 100 Various skin lesions like those in collagen row transplantation. Differential diagnosis from
days diseases and lichen planus. Liver dysfunc- drug eruption is almost impossible clinically. b,
tion, oral symptoms, ocular symptoms. c: Severe acute GVHD. Severe exfoliation simi-
lar to toxic epidermal necrolysis is seen.
Transfusion- About 10 days Resemble those of hyperacute GVHD.
associated Prognosis is poor.
 134 10 Drug-Induced Skin Reactions and GVHD

Table 10.5 Clinical staging and grading of GVHD.

Liver findings
Stage Skin findings Gut findings
(mg/dL bilirubin)
1 Maculopapular rash on 2 to 3 Diarrhea 500 to
<25% of body surface 1000 mL/d or
persistent nausea
2 Maculopapular rash on 25% 3 to 6 Diarrhea 1000 to
to 50% of body surface 1500 mL/d
3 Generalized erythroderma 6 to 15 Diarrhea >1500
Clinical images are available mL/d
in hardcopy only.
4 Desquamation and bullae >15 Severe abdominal
pain or ileus
Stage
Overall Grade
Skin Liver Gut Functional impairment
0 (None) 0 0 0 0
I (Mild) 1 to 2 0 0 0
10
II (Moderate) 1 to 3 1 1 1
c d e f g h i j k l
III (Severe) m n3
2 to 2oto 3 p2 to 3 q r 2
IV (Life-threatening) 2 to 4 2 to 4 2 to 4 3
(Adapted from; http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed6.table.
17337).

vacuolar degeneration of the basal cell layer are found (Chapter

2). The number of Langerhans cells decreases.

Differential diagnosis
Clinical images are available GVHD needs to be differentiated from drug-induced skin reac-
in hardcopy only.
tions, eruptions of peripheral lymphocyte recovery accompany-
ing a graft (generally 10 to 14 days after transplant), and viral
infections.

Treatment
Immunosuppressants (cyclosporine, tacrolimus, azathioprine,
cyclophosphamide) and steroids are administered orally, Post-
transfusion GVHD can be prevented by irradiating the blood to
d e f g h i j k l m n o p q r
be transfused.
Fig. 10.8-2 Acute graft-versus-host disease
(GVHD).
d, e: Diffuse small erythema coalesce into red 2. Viral eruption
plaques.
When maculopapular erythema appear abruptly on the whole
body of a febrile patient who has been adiministered NSAIDs or
any other medicine for that condition, a drug reation or a viral
infection are the two most likely diagnoses. In those cases, differ-
entiation between drug-induced eruption and viral eruption is
often difficult, even with thorough examination. Drug-induced
hypersensitivity syndrome (DIHS) is thought to be caused by
causative drug as well as re-activation of latent viral infection.
Refer to Chapter 23 for details on viral infections.

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