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Dermatologica Sinica: Cheng-Han Lee, Yi-Chun Chen, Yung-Tsu Cho, Chia-Ying Chang, Chia-Yu Chu
Dermatologica Sinica: Cheng-Han Lee, Yi-Chun Chen, Yung-Tsu Cho, Chia-Ying Chang, Chia-Yu Chu
Dermatologica Sinica
journal homepage: http://www.derm-sinica.com
ORIGINAL ARTICLE
Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Department of Dermatology, Cathay General Hospital, Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received: Jul 19, 2011
Revised: Oct 4, 2011
Accepted: Feb 9, 2012
Keywords:
generalized bullous xed drug eruption
xed drug eruption
Stevens-Johnson syndrome
toxic epidermal necrolysis
Introduction
Fixed drug eruptions (FDEs) are dened as recurrent lesions at
the same skin or mucosal sites after repeated intake of the causative agent.1 FDEs usually present as itching or burning, wellcircumscribed, erythematous macules, patches, or plaques that
leave hyperpigmentation after resolving. Vesicles or bullae may
occasionally be seen. There are many causative agents and the
incidence of FDE for a particular drug depends on the frequency of
its use. Therefore, the list of etiologic drugs varies from one place to
another and from time to time.2
1027-8117/$ e see front matter Copyright 2012, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.dsi.2012.02.002
12
bright red or dusky red macules that might evolve into an edematous
plaque with residual grayish or slate-colored hyperpigmentation
(Figure 1A).3 GBFDE was dened as typical or nonpigmented FDE
lesions with bulla formation involving at least three of the following
different anatomic sites: head and neck (including lips), anterior
trunk, back, upper limbs, lower limbs, and genitalia (Figure 1B).4e7
Patch tests were performed according to ICDRG regulations
and literature after obtaining informed consent.8,9 Due to ethical
issues, oral challenge tests were not performed. Clinical data, suspected etiologies, and pathology/patch test results were collected
from chart records. Pathology-proved TEN or SJS/TEN overlap
patients in the same period were included to compare with GBFDE
patients. These TEN or SJS/TEN overlap patients were diagnosed
according to the criteria proposed by the European Registry of
Severe Cutaneous Adverse Reactions (EuroSCAR) group.10 Pathologic features such as supercial or supercial and deep inammation, basal vacuolization, pigment incontinence, and presence of
dyskeratotic (apoptotic) keratinocytes were recorded. Eosinophil
and neutrophil numbers were also assessed on a four-point scale
[score of 0 indicated no specied cell in the specimen; score 1, < 2
cells in every 400 high power eld (HPF); score 2, 2e10 cells in
one HPF; and score 3, > 10 cells in one HPF].
Statistical analysis
Two-sided Wilcoxon rank sum test was used to compare the age
difference of GBFDE and non-GBFDE patients. Chi-square tests or
Figure 1 (A) Fixed drug eruption: round erythematous plaque with central dusky red
to grayish hyper-pigmentation; (B) generalized bullous xed drug eruption: large areas
of accid blisters or erosions involving the abdomen, thighs, and glans penis.
Total (%)
Non-GBFDE (%)
GBFDE (%)
p value
Number
Age (mean SD), y
Median age
Sex (W/M)
Previous events
39
52.2 24.4
56
17/22
20 (51.3)
30
47.2 23.6
46
14/16
14 (46.7)
9
69.1 19.7
74
3/6
6 (66.7)
NA
0.0124
NA
0.7042
0.4506
Location
Mucosal involvement
Lip or oral mucosa
Genital area
15 (38.5)
12 (30.8)
8 (20.5)
9 (30.0)
8 (26.7)
5 (16.67)
6 (66.67)
4 (44.4)
3 (33.33)
0.0631
0.4161
0.3548
Extremities
Hands
Other extremities
Trunk
Face
Patch test (/)
13 (33.3)
28 (71.8)
20 (51.3)
6 (15.4)
4/8
9 (30.0)
20 (66.7)
12 (40.0)
3 (10.0)
3/5
4 (44.4)
8 (88.89)
8 (88.89)
3 (33.3)
1/3
0.4472
0.3994
0.0197
0.1225
NA
13
NSAIDs
Antibiotics
Other drugs
Multiple drugs
Other etiologies
Unknown
Non-GBFDE (n 30)
GBFDE (n 9)
Total
1 (ibuprofenb)
3 (ceftriaxonea, cefpiromeb, tetracyclineb)
1 (allopurinolb)
5
4
7
FDE xed-drug eruption; GBFDE generalized bullous xed drug eruption; NSAID nonsteroidal anti-inammatory drug.
a
Positive patch test.
b
Previous events ().
c
Negative patch test.
Table 3 Comparison of clinical and pathologic features GBFDE and SJS/TEN overlap
or TEN.
GBFDE (%)
Clinical features
Average age (mean SD), y
Median age, y
Sex (W/M)
Previous events
Mucosal involvement
Constitutional symptoms
n9
69.1 19.7
74
3/6
6 (66.7)
6 (66.7)
1 (11.1)
n6
58.7 26.1
57.5
3/3
0 (0)
6 (100)
3 (50)
Pathologic features
Perivascular inammation
Supercial
Supercial and deep
Basal vacuolization
Fire ag signa
Eosinophil scoreb
0
1
2
Neutrophil scoreb
0
1
2
Pigment incontinence
n7
n6
5
2
7
0
6
0
6
6
(71.4)
(28.6)
(100)
(0)
(100)
(0)
(100)
(100)
0 (0)
3 (42.9)
4 (57.1)
3 (50)
3 (50)
0 (0)
6
0
1
7
4
2
0
2
(85.7)
(0)
(14.3)
(100)
(66.7)
(33.3)
(0)
(33.3)
GBFDE generalized bullous xed drug eruption; HPF high power eld; NA, not
applicable; SD standard deviation; SJS Stevens-Johnson syndrome; TEN toxic
epidermal necrolysis.
a
Fire ag sign, more than two aggregated dyskeratotic keratinocytes.
b
0, no specied cell in the specimen; 1, specied cell present but < 2 cells in
every 400 HPF; 2, 2e10 cells in one HPF; 3, > 10 cells in one HPF.
By contrast, GBFDE specimens showed no aggregated dyskeratotic keratinocytes in the epidermis (re ag sign) (0%), frequent
pigment incontinence (100%), more common supercial and deep
perivascular inammation (28.6%), and higher eosinophil scores
(1e2). These results are shown in Figure 2C and D. Such results
indicated that detailed histopathologic examination from early
stage lesions or perilesional skin, along with clinical information
of previous episodes, constitutional symptoms, and mucosal
involvement, were useful in differentiating GBFDE from SJS/TEN.
Discussion
This study collected 39 cases of FDE from a referral center in
northern Taiwan. NSAIDs and antibiotics are the most common
drugs causing FDE among many other etiologies. Patients with
GBFDE are older and have higher chances of trunk and mucosal
involvement than non-GBFDE patients. Patients with GBFDE are
also more likely to have previous events but less likely to have
constitutional symptoms than patients with SJS/TEN overlap or
TEN. The presence of eosinophils and pigment incontinence with
absent re ag sign is an important clue to differentiate GBFDE
from SJS/TEN.
Although the rst case of FDE was described by Bourns in
1889,13 the term FDE was rst proposed in 1894 by Brocq to
describe a special type of reaction to antipyrine.14 The phenomenon
of lesions recurring at the previous involved sites has intrigued
many dermatologists. Intraepidermal CD8 T cells with effectormemory phenotype resident in FDE lesions are considered very
important in the disease pathogenesis. FDE predisposing sites (i.e.
lips, genital areas, or hands) are frequent regions of herpes simplex
virus (HSV) reactivation.15 Previous studies have found that the vast
majority of FDE patients are asymptomatic HSV seropositive individuals and their anti-HSV immunoglobin G (IgG) titers are much
higher than in patients with HSV recurrences.15 FDE lesions found
at previously traumatized sites, such as burn scars and insect bites,
were also well documented.15 Moreover, these T cells are found at
the site of repeated pathogen entry, such as the lungs. Thus,
intraepidermal CD8 T cells with an effector-memory phenotype
resident in FDE lesions may mediate protective immunity.15 Additional recruitment of other inammatory cells occurs in the late
stage of the disease, and then disease activity is down regulated by
regulatory T cells.15
A recent French study16 recruited 59 cases from 17 hospitals
over three years, which indicate that FDE is not a common cutaneous adverse drug reaction (roughly one case per year per
hospital). However, FDEs are the most frequent cutaneous reactions
14
Figure 2 Pathologic features of toxic epidermal necrolysis (TEN) and generalized bullous xed drug eruption (GBFDE). (A, B) TEN: supercial perivascular lymphocytic inammation, aggregation of more than two dyskeratotic keratinocytes (re ag sign, arrows), and basal vacuolization (hematoxylin-eosin, 40 and 100); (C) GBFDE: discrete
dyskeratosis, basal vacuolization, and supercial perivascular lymphocytic inammation (hematoxylin-eosin, 100; (D) GBFDE: pigment incontinence and eosinophils in the upper
dermis (hematoxylin-eosin, 200).
15