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Drug-Induced Skin Reactions and GVHD
10
Skin and mucocutaneous lesions induced by a drug or by its metabolites are called drug eruptions. Some cutaneous 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 patient’s 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.
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b
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General information
Maculopapular or morbilliform eruptions may be the most common of all cutaneous drug reactions. It is also known that cutaneous drug reactions present the specific morphological patterns.
(Figs. 10.1-1 and 10.1-2). In diagnosing skin diseases, it is essential 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,
porgansq
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l disfunction
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nof the internal
o
fever,
lymph
node
enlargement,
such as liver, kidneys or bone marrow, hypotension and shock.
Classification, Pathogenesis
Drug eruptions are roughly divided into immunologic and nonimmunologic. 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 serious cases, such as anaphylactic shock, systemic management
using steroids in large doses including antihistamines, epinephrines, and steroids in large doses, including by pulse therapy.
a
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Fig. 10.1-1 Drug-induced skin reaction.
a: Diffuse edematous erythema on the back. Each
eruption is an erythema multiforme-like erythema of 1 cm to 2 cm in diameter that gradually
enlarged and tended to coalesce. b: Edematous
itchy erythema coalesced into a large plaque.
i a.
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Classification
ofmdrugn eruptions
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pathogenesis (Table 10.2)
r
1. Immunologic drug reactions
A drug or the complex of a drug and a serum protein becomes
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127
A. Drug-induced skin reactions
Table 10.1 Drug-induced skin reactions and their typical causative drugs.
Type of eruption in druginduced reactions
Causative drugs
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
(TEN)
Cefzonam, penicillin, phenobarbital, chlormezanone, carbamazepine, methazolamide, acetaminophen,
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
Eczematous
Penicillin, chlorpromazine, chlorthiazide, promethazine
Purpuric
Sodium aurothiomalate, sulfamethoxazole, penicillin, aspirin
antigenic, causing a drug eruption that results from immunological processes. That is, a drug eruption occurs in specific individuals 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 anaphylactic shock occurs.
Type II allergy: Complements are activated by an antigenic drug
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 complex deposits in tissues, causing disorders. Vasculitic eruptions
are thought to be caused by this mechanism.
Type IV allergy: A delayed hypersensitivity reaction is induced
by T cells that have been sensitized to drug antigens. It isa knownb
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.
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Clinical images are available
in hardcopy only.
2. Non-immunologic drug-induced skin
reactions
Drug-induced skin reactions without an immunologic pathogenesis may affect anyone, regardless of whetherathere has
b beenc
sensitization.The pathogenesis of drug-induced skin reactions can
also be classified pharmacokinetically.
Pharmacologic effects: Drug-induced skin reactions may be produced by essential pharmacological action of the drug. Hair loss
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Fig. 10.1-2 Drug-induced skin reaction.
c: Drug-induced erythema enlarged and coalesced to form erythroderma. d: Drug eruption
caused by tegafur.
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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)
Type IV hypersensitivity (reactions caused by activated T cells)
Clinical images are available
in hardcopy only.
Non-immunologic
Pharmacological effects
Accumulation
Drug interaction
Patient-specific conditions
a
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Clinical images are available
in hardcopy only.
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caused by anticancer agents and exfoliation in palms and soles
caused by retinoids are examples.
Accumulation: A drug accumulates in the skin or mucous membranes from prolonged use (arsenic melanoderma and argyria are
examples of accumulation disorders).
Drug interaction: One drug may inhibit another drug’s metabolism 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
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cause
drug
reactions;
excessive
occurs
against
a qminuter
amount of drug (intolerance). An unexpected action of the drug is
caused (idiosyncrasy).
b. Classification of drug eruptions by
characteristic skin features
Although maculopapular eruption (multiple edematous erythema on the extremities and trunk) are the most common;
drug-induced skin reactions can appear as any kind of cutaneous lesion (Table 10.1). When seeing patients with any
types of eruption, dermatologists should always carefully consider the possibility of precedent drug reactions.
Clinical images are available
in hardcopy only.
c. Methods of identifying the causative
drug
b
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Fig. 10.2-1 Various types of drug-induced
skin reaction.
a, b: Erythema multiforme-like. Although uniformly colored erythematous plaques are mainly
seen, newly formed erythema is seen at the
periphery, some parts of which show the targetlike appearance that characterizes erythema multiforme. c: Purpuric. Dark red macules up to 1
cm in diameter are observed. These do not disappear by diascopy pressure, which indicates that
the eruption is purpura.
History is taken on drug-induced skin reactions and on exacerp
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n influenced
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r
bation
or
ofmeruptions
by useqor discontinuation of a drug. If the eruption is suspected to be drug-induced
reactions, tests listed below are conducted for identification
(Chapter 5).
①Skin test (scratch test, prick test, intradermal test)
②Patch test
③Drug lymphocyte stimulation test (DLST)
④Rechallenge test (absolutely contrainidicated in severe forms
of drug reactions)
r
129
A. Drug-induced skin reactions
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 frequently 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
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 seva
b of thec
eral minutes to several hours after the administration
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-imflammatory pigmentation).
Clinical images are available in hardcopy only.
10
d
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
food additives.
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Clinical images are available in hardcopy only.
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
The causative drug should be discontinued.
b
c
d
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 syndrome and transitional forms correspond to the same syndrome,
but with less extensive skin detachment and a lower mortality (515%).
Hypersensitivity syndrome, sometimes called drug-induced
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Fig. 10.2-2 Various types of drug eruption.
d, e: Urticarial drug eruptions. Edematous erythema resembling urticaria is seen on the trunk and
palms.
Generalized bullous
fixed drug eruption
MEMO
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 categorized with toxic epidermal necrolysis (TEN),
which is described in the following section.
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Drug-Induced Skin Reactions and GVHD
Clinical images are available
in hardcopy only.
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Clinical images are available in hardcopy only.
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Clinical images are available in hardcopy
only.
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b
Clinical images are available
in hardcopy only.
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Clinical images are available in hardcopy only.
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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: Lyell’s syndrome
Clinical images are available in hardcopy only.
Fig. 10.4-1 Toxic epidermal necrolysis (TEN).
Clinical features, Classification
Toxic epidermal necrolysis (TEN) is one of the severest drug
eruptions. It is accompanied by fever, and erythema and blistering 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 primary 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
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A. Drug-induced skin reactions
fixed drug
eruption
(FDE)
generalized
FDE
TEN
SJS
EM
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).
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
large burn (second-degree). This type accounts for several percent of all TEN cases (Fig. 10.6).
Fig. 10.4-2 Toxic epidermal necrolysis (TEN).
10
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 separation 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 therapy, 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 topical 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.
Clinical images are available in hardcopy only.
a
2) Drug-induced hypersensitivity syndrome
b
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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
concept of the disease condition, but each different disease namea
may indicate the same or similar condition which is induced by
drug. Drug-induced hypersensitivity syndrome (DIHS) is proposed
by a group of Japanese dermatologists which holds that skin lesions
are caused by a combination of drug allergy and reactivated latent
viral infection, specifically human herpes virus 6 (HHV 6) infection. Two to 6 weeks after administration of a specific drug, fever
b
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Fig. 10.6 Diffuse erythematous toxic epidermal necrolysis (Lyell's syndrome).
a: The causative drugs here are antituberculosis
drugs, which were used for tuberculosis associated with AIDS. Generalized shedding of the epidermis on the whole body is seen. The dermis is
pink where the skin exfoliates. b: Severe erosions
and ulcers in the oral region.
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Drug-Induced Skin Reactions and GVHD
Table 10.3 Diagnostic criteria for drug-induced hypersensitivity
syndrome (DIHS).
Clinical images are available in hardcopy only.
1. Maculopapular rash develops more than 3 weeks after starting a certain
drugs.
2. Lymphadenopathy
3. Fever (>38˚C)
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 antiviral and antidrug immune responses. Allergology International 2006; 55: 1-8).
10
Clinical images are available in hardcopy only.
Fig. 10.7 Drug-induced hypersensitivity
syndrome (DIHS).
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 (HHV7) 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 termination of the causative drug.
B. GVHD and viral eruptions
1. Graft-versus-host disease (GVHD)
Outline
● After
bone marrow transplantation, other organ transplantation or transfusion, donor lymphocytes are stimulated by major and/or minor histocompatibility locus
antigens and subsequently target host tissues for cytotoxic 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.
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B. GVHD and viral eruptions
Definition, Pathogenesis
When donor-derived blood cells circulate in the patient’s skin
after transplantation, the immunocompetent donor, T cells, may
recognize the foreign hosts histocompatibility locus antigens
(HLA). Subsequently, an immune reaction against the host’s
organs occurs. It may also be caused by general blood transfusions.
Classification
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
after birth, and intractable dermatitis, diarrhea, opportunistic
infections, and disturbance in growth are caused by lymphocytes
transferred from the mother.
Clinical features
Acute GVHD: In most cases, 10 to 30 days after a graft, edematous erythema appears on the extremities and trunk. It may be
accompanied by slight itching. In severe cases, the eruptions coalesce and may develop into erythroderma, blistering or erosion
(Figs. 10.8-1 and 10.8-2). Symptoms of acute GVHD may
remain longer even after the first 100 days or more after transplantation, as a result of recent improvements in immunosuppressive drugs.
Chronic GVHD: This includes lichenoid forms and sclerodermoid 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).
a
Clinical images are available in hardcopy only.
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Pathology
GVHD pathologically presents a lichenoid reaction. Intradermal lymphocyte infiltration, necrosis of the epidermal cells, and
Table 10.4 Classification of graft-versus-host disease (GVHD).
Type of
GVHD
Duration after
transplantation/
transfusion
Symptoms
Fever, diarrhea, erythrodermic skin eruption, pulmonary edema, heart failure
Hyperacute
7 to 14 days
Acute
a
b
Up to 100 days Triad (fever, diarrhea and liver dysfunction).
Poorly demarcated erythema seen on the
face and palmoplantar area. In severe
cases, TEN and erythroderma.
Chronic
More than 100 Various skin lesions like those in collagen
diseases and lichen planus. Liver dysfuncdays
tion, oral symptoms, ocular symptoms.
Transfusion- About 10 days
associated
Clinical images are available in hardcopy only.
Resemble those of hyperacute GVHD.
Prognosis is poor.
c
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Fig. 10.8-1 Acute graft-versus-host disease
(GVHD).
a: Diffuse erythema on the back after bone marrow transplantation. Differential diagnosis from
drug eruption is almost impossible clinically. b,
c: Severe acute GVHD. Severe exfoliation similar to toxic epidermal necrolysis is seen.
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Drug-Induced Skin Reactions and GVHD
Table 10.5 Clinical staging and grading of GVHD.
Clinical images are available
in hardcopy only.
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Gut findings
1
Maculopapular rash on
<25% of body surface
2 to 3
Diarrhea 500 to
1000 mL/d or
persistent nausea
2
Maculopapular rash on 25%
to 50% of body surface
3 to 6
Diarrhea 1000 to
1500 mL/d
3
Generalized erythroderma
6 to 15
Diarrhea >1500
mL/d
4
Desquamation and bullae
>15
Overall Grade
10
Liver findings
(mg/dL bilirubin)
Skin findings
Stage
Severe abdominal
pain or ileus
Stage
Skin
Liver
Gut
Functional impairment
0 (None)
0
0
0
0
I (Mild)
1 to 2
0
0
0
II (Moderate)
1 to 3
1
1
1
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III (Severe)
IV (Life-threatening)
n3
2 to
2oto 3
2 to 4
2 to 4
p2 to 3 q
2 to 4
r
2
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
GVHD needs to be differentiated from drug-induced skin reactions, eruptions of peripheral lymphocyte recovery accompanying a graft (generally 10 to 14 days after transplant), and viral
infections.
Clinical images are available
in hardcopy only.
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Fig. 10.8-2 Acute graft-versus-host disease
(GVHD).
d, e: Diffuse small erythema coalesce into red
plaques.
Treatment
Immunosuppressants (cyclosporine, tacrolimus, azathioprine,
cyclophosphamide) and steroids are administered orally, Posttransfusion GVHD can be prevented by irradiating the blood to
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transfused.
2. Viral eruption
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, differentiation 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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