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ORIGINAL ARTICLE
Fixed-drug eruption A retrospective study in a single referral center
in northern Taiwan
Cheng-Han Lee 1 Yi-Chun Chen 2 Yung-Tsu Cho 1 Chia-Ying Chang 1 Chia-Yu Chu 1
1 Department of Dermatology National Taiwan University Hospital and National Taiwan University College of Medicine Taipei Taiwan2 Department of Dermatology Cathay General Hospital Taipei Taiwan
a r t i c l e i n f o
Article history
Received Jul 19 2011
Revised Oct 4 2011
Accepted Feb 9 2012
Keywords
generalized bullous 1047297xed drug eruption
1047297xed drug eruption
Stevens-Johnson syndrome
toxic epidermal necrolysis
a b s t r a c t
BackgroundObjective Fixed drug eruption (FDE) is a dermatosis characterized by recurrent patches or
plaques at exactly the same sites with each administration of the causative drug Vesicles or bullae may
sometimes be found and generalized bullous 1047297xed drug eruption (GBFDE) may be confused with
Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) This study aimed to investigate the
clinical and pathologic features of FDE in Taiwan
Methods A retrospective analysis evaluated patients with FDE in a referral center in Taiwan covering
a period of 11 years Clinical data suspected etiologies and pathologypatch test results were collected
We also compared the GBFDE cases with SJSTEN overlap or TEN cases to 1047297nd differentiating clues
Results There were 39 FDE patients including nine GBFDE cases The most frequent causative drugs were
non-steroidal anti-in1047298ammatory drugs (1047297ve cases 128) and antibiotics (four cases 103) Extremities
other than the hands (718) were the most frequently affected sites followed by the trunk (513)
mucosa (385) and hands (333) The average age of FDE patients was 522 years (median 56 years
range 4e86 years) Patients with GBFDE were signi1047297cantly older than non-GBFDE patients (691 197
vs 472 236 pfrac14 00124) and the trunk was more likely to be involved in GBFDE cases (889 vs 400
pfrac14 00197) GBFDE cases also showed tendency to have more mucosal involvement (667 vs 300
pfrac14 00631) Although similar to SJSTEN GBFDE cases had fewer constitutional symptoms less mucosalinvolvement but had previous episodes Histopathologically the presence of more than two aggregated
dyskeratotic keratinocytes (1047297re 1047298ag sign) in the epidermis was more frequently observed in SJSTEN
whereas GBFDE had super1047297cial and deep dermal in1047297ltration of eosinophils and melanophages
Conclusion FDE is one of the specialized cutaneous drug reactions and GBFDE should be kept in mind and
differentiated from SJSTEN
Copyright 2012 Taiwanese Dermatological Association
Published by Elsevier Taiwan LLC All rights reserved
Introduction
Fixed drug eruptions (FDEs) are de1047297ned as recurrent lesions at
the same skin or mucosal sites after repeated intake of the causa-
tive agent1
FDEs usually present as itching or burning well-circumscribed 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 time2
Generalized bullous 1047297xed drug eruption (GBFDE) may be
confused with toxic epidermal necrolysis (TEN) or Stevens-Johnson
syndrome (SJS) The present study aimed to investigate the clinical
and pathologic features of FDE in Taiwan and identify several
differentiating features between GBFDE and non-GBFDE as well asbetween GBFDE and SJSTEN
Methods
Patients
From January 2000 to February 2011 cases with suspected diagnosis
of FDE recorded in the patch-testing database or skin pathology
database of the Department of Dermatology of the National Taiwan
University Hospital in Taipei Taiwan were recruited FDE was
diagnosed according to the typical clinical features erythematous
Corresponding author Chia-Yu Chu Department of Dermatology National
Taiwan University Hospital Number 7 Chung-Shan South Road Taipei Taiwan
E-mail address chiayuntuedutw (C-Y Chu)
Contents lists available at SciVerse ScienceDirect
Dermatologica Sinica
j o u r n a l h o m e p a g e h t t p w w w d e r m- s i n i c a c o m
1027-8117$ e see front matter Copyright 2012 Taiwanese Dermatological Association Published by Elsevier Taiwan LLC All rights reserved
doi101016jdsi201202002
DERMATOLOGICA SINICA 30 (2012) 11e15
8102019 1e327b
httpslidepdfcomreaderfull1e327b 25
brightred ordusky red macules that might evolve into an edematous
plaque with residual grayish or slate-colored hyperpigmentation
(Figure 1A)3 GBFDE was de1047297ned 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 consent89 Due to ethical
issues oral challenge tests were not performed Clinical data sus-
pected etiologies and pathologypatch test results were collected
from chart records Pathology-proved TEN or SJSTEN overlap
patients in the same period were included to compare with GBFDE
patients These TEN or SJSTEN overlap patients were diagnosed
according to the criteria proposed by the European Registry of
Severe Cutaneous Adverse Reactions (EuroSCAR) group10 Patho-
logic features such as super1047297cial or super1047297cial and deep in1047298am-
mation 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 speci1047297ed cell in the specimen score 1 lt 2
cells in every 400 high power 1047297eld (HPF) score 2 2e10 cells in
one HPF and score 3 gt 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
Fisherrsquos exact tests were conducted to compare differences in sex
frequency of previous events and lesion locations between the two
groups All of the statistical analyses were performed using the SAS
software (ver 913 SAS Institute Cary NC USA)
Results
FDE patients including GBFDE and non-GBFDE
Of the 39 FDE patients recruited in this study 30 were non-GBFDE
and nine were GBFDE cases (Table 1) The average age of FDE
patients was 522244 years (median 56 years range 4e86
years) The average and median ages of non-GBFDE were younger
than those of GBFDE (472 236 vs 691197 years pfrac1400124
and 46 vs 74 years) There was no signi1047297cant sex preference
although a trend of male predominance was noted (22 men and 17
women) A total of 20 of the 39 FDE patients (513) had previous
events including 14 (467) non-GBFDE and six (667) GBFDE
( pfrac1404506)
Fifteen FDE patients (385) had mucosal involvement GBFDE
cases seemed more likely to have mucosal lesions (667 vs non-
GBFDE 300 pfrac14 00631) GBFDE patients were also more likely
to have trunk involvement (889 in GBFDE vs400 in non-GBFDE pfrac1400197) These results are shown in Table 1
Etiologic agents
Nonsteroidal anti-in1047298ammatory drugs (NSAIDs) were the most
common causative agents accounting for 128 of cases (1047297ve cases
including four non-GBFDEand one GBFDE) Four cases (103) were
caused by antibiotics (one non-GBFDE and three GBFDE) Other
cases were caused by miscellaneous agents including computed
tomography contrast and unknown Chinese herbal drugs (Table 2)
During this period only 12 of the 39 patients received patch testing
of the suspected causative agents on the previous lesion sites four
(333) of whom had a positive reaction to the suspected drugs
GBFDE and TEN
Four TEN patients and two SJSTEN overlap patients were included
for comparison with GBFDE patients (Table 3) The GBFDE patients
were older than the SJSTEN overlap or TEN patients (691197 vs
587261 years median 74 vs 575 years) Previous events were
noted in six GBFDE patients (667) but none in the SJSTEN overlap
or TEN patients There was mucosal involvement in six GBFDE
Figure 1 (A) Fixed drug eruption round erythematous plaque with central dusky red
to grayish hyper-pigmentation (B) generalized bullous 1047297xed drug eruption large areas
of 1047298
accid blisters or erosions involving the abdomen thighs and glans penis
Table 1 Demographic data of patients with non-GBFDE and GBFDE
Total () Non-GBFDE () GBFDE () p value
Number 39 30 9 NA
Age (mean SD) y 522244 472236 691197 00124Median age 56 46 74 NA
Sex (WM) 1722 1416 36 07042
Previous events 20 (513) 14 (467) 6 (667) 04506
Location
Muco sal i nvo lve ment 15 (385) 9 (30 0) 6 ( 6667) 00631
Lip or oral mucosa 12 (308) 8 (267) 4 (444) 04161
Genital area 8 (205) 5 (1667) 3 (3333) 03548
Extremities
Hands 13 (333) 9 (300) 4 (444) 04472
Other extremi ti es 28 (718) 20 ( 667) 8 ( 8889) 03994
Trunk 20 (513) 12 (400) 8 (8889) 00197
Face 6 (154) 3 (100) 3 (333) 01225
Patch test (thorn) 48 35 13 NA
GBFDEfrac14 generalized bullous 1047297xed drug eruption NAfrac14 not applicable SDfrac14
standard deviation
C-H Lee et al Dermatologica Sinica 30 (2012) 11e1512
8102019 1e327b
httpslidepdfcomreaderfull1e327b 35
patients (667) and in all six SJSTEN overlap or TEN patients
Constitutional symptoms (eg fever chills or malaise) were more
common in SJSTEN overlap or TEN patients [three patients (50)
vs one in GBFDE (111)]To avoid examining secondary changes of skin pathology due to
blister formation or epidermal necrosis only biopsy specimens
taken from the perilesional skin or early stage lesions were used
for comparison of histopathologic features between GBFDE and
SJSTEN Seven and six histologic specimens were available for
evaluation in GBFDE and SJSTEN overlap or TEN patients respec-
tively The pathologic features of SJSTEN overlap or TEN specimens
showed super1047297cial perivascular in1047298ammation (100) basal
vacuolization (100) presence of 1047297re 1047298ag sign31112 (more than two
aggregated dyskeratotic keratinocytes 100) less pigment incon-
tinence (333) and lower eosinophil score (0e1) These results are
shown in Figure 2A and B
By contrast GBFDE specimens showed no aggregated dysker-
atotic keratinocytes in the epidermis (1047297re 1047298ag sign) (0) frequent
pigment incontinence (100) more common super1047297cial and deep
perivascular in1047298ammation (286) 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 SJSTEN
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 haveconstitutional symptoms than patients with SJSTEN overlap or
TEN The presence of eosinophils and pigment incontinence with
absent 1047297re 1047298ag sign is an important clue to differentiate GBFDE
from SJSTEN
Although the 1047297rst case of FDE was described by Bourns in
188913 the term FDE was 1047297rst proposed in 1894 by Brocq to
describe a special type of reaction to antipyrine14 The phenomenon
of lesions recurring at the previous involved sites has intrigued
many dermatologists Intraepidermal CD8thorn T cells with effector-
memory phenotype resident in FDE lesions are considered very
important in the disease pathogenesis FDE predisposing sites (ie
lips genital areas or hands) are frequent regions of herpes simplex
virus (HSV) reactivation15 Previous studies have found that the vast
majority of FDE patients are asymptomatic HSV seropositive indi-viduals and their anti-HSV immunoglobin G (IgG) titers are much
higher than in patients with HSV recurrences15 FDE lesions found
at previously traumatized sites such as burn scars and insect bites
were also well documented15 Moreover these T cells are found at
the site of repeated pathogen entry such as the lungs Thus
intraepidermal CD8thorn T cells with an effector-memory phenotype
resident in FDE lesions may mediate protective immunity15 Addi-
tional recruitment of other in1047298ammatory cells occurs in the late
stage of the disease and then disease activity is down regulated by
regulatory T cells15
A recent French study16 recruited 59 cases from 17 hospitals
over three years which indicate that FDE is not a common cuta-
neous adverse drug reaction (roughly one case per year per
hospital) However FDEs are the most frequent cutaneous reactions
Table 2 Suspected etiologies of FDE
Non-GBFDE (nfrac14 30) GBFDE (nfrac14 9) Total
NSAIDs 4 (mefenamic acidab sulindacab piroxicamab acemetacin) 1 (ibuprofenb) 5
Antibiotics 1 (cephalosporin) 3 (ceftriaxonea cefpiromeb tetracyclineb) 4
Other drugs 6 (rabeprazolebc levamisoleb allopurinolb propranolol Andrographis paniculatab
dicyclomine or mepenzolateb)
1 (allopurinolb) 7
Multiple drugs 7 [(doxycycline acetaminophenbc) (sulfamethoxazole and trimethoprim
diclofenacbc) (sulfamethoxazole and trimethoprim diclofenacbc) (clindamycin
sulfamethoxazole and trimethoprim ibuprofen pseudoephedrineb) (amoxicillinmefenamic acidb) (cephalexin levocetirizineb)(diclofenac indomethacin colchicin
allopurinolb)]
2 [(sulindac cimetidine calcium carbonatebc)
(amoxicillin hydroxyzine mefenamic acida)]
9
Other etiologies 5 [computed tomography contrast unknown Chinese herbal drugsb drug for headache
drugs for upper respiratory tract infection (two cases)]
0 5
Unknown 7 2 9
FDEfrac14 1047297xed-drug eruption GBFDEfrac14 generalized bullous 1047297xed drug eruption NSAIDfrac14nonsteroidal anti-in1047298ammatory druga Positive patch testb Previous events (thorn)c Negative patch test
Table 3 Comparison of clinical and pathologic features GBFDE and SJSTEN overlap
or TEN
GBFDE () SJSTEN overlap or TEN ()
Clinical features nfrac149 nfrac146
Average age (mean SD) y 691197 587261
Median age y 74 575
Sex (WM) 36 33
Previous events 6 (667) 0 (0)
Mucosal involvement 6 (667) 6 (100)
Con sti tuti onal symptoms 1 (111) 3 (50)
Pathologic features nfrac147 nfrac146
Perivascular in1047298ammation
Super1047297cial 5 (714) 6 (100)
Super1047297cial and deep 2 (286) 0 (0)
Basal vacuolization 7 (100) 6 (100)
Fire 1047298ag signa 0 (0) 6 (100)
Eosinophil scoreb
0 0 (0) 3 (50)
1 3 (429) 3 (50)
2 4 (571) 0 (0)
Neutrophil scoreb
0 6 (857) 4 (667)
1 0 (0) 2 (333)
2 1 (143) 0 (0)
Pigment incontinence 7 (100) 2 (333)
GBFDEfrac14 generalized bullous 1047297xed drug eruption HPFfrac14 high power 1047297eld NA not
applicable SDfrac14 standard deviation SJSfrac14 Stevens-Johnson syndrome TENfrac14 toxic
epidermal necrolysisa Fire 1047298ag sign more than two aggregated dyskeratotic keratinocytesb 0 no speci1047297ed cell in the specimen 1 speci1047297ed cell present but lt 2 cells in
every
400 HPF 2 2e
10 cells in one HPF 3gt
10 cells in one HPF
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 13
8102019 1e327b
httpslidepdfcomreaderfull1e327b 45
in one report from India accounting for 30 of all cutaneous
adverse drug reactions (61 cases over a 10-year study)17 There
werea total of 39 cases overan 11-year period in one referral center
for drug eruption and patch testing in northern Taiwan It seems
that the incidence rate of FDE in Taiwan is similar to that of IndiaThere may be some evidence of genetic predisposition to FDEs1
The average age of the patients in the current study is 522 years
which is older than those of previous reported series (around the
fourth decade)18e20 However the median age of one recent study
(58 years) is close to the present 1047297ndings16 The average age of
GBFDE patients is higher than those of non-GBFDE patients This
may be explained by the fact that GBFDE patients have more
previous episodes than non-GBFDE patients even though the
difference is not statistically signi1047297cant It is possible that some
patients may overlook or forget prior episodes
Some studies including the present one show a trend toward
a male predominance2 although female predominance has also
been reported16 In the present study extremities (not including
hands)(718) were the most frequently affected sites followed bytrunk (513) mucosa (385) and hands (333) In a study of site
involvement in FDE from 105 patients from Turkey genital mucosa
(505) was the most frequently involved site followed by the
trunk (381) lips (371) and hands (324)20 However some
studies show that the lips are the most frequently affected
site181921
The etiology of FDE varies depending on the drugs in vogue at
the time in different regions2 The list of causative drugs is long
including non-narcotic analgesics antibacterial agents antifungal
agents antipsychotics other miscellaneous drugs and even ultra-
violet radiation emotional and psychiatric factors heat menstrual
abnormalities pregnancy fatigue cold and undue effort2 There is
even one report describing a male patient with postcoital FDE after
his wife took the causative drug trimethoprimsulfamethoxazole
22
In the present study the etiologies are diverse It is very common
that patients take several drugs at one time and in this study nine
patients took multiple possible drugs Therefore it is dif 1047297cult to
identify the true etiology Furthermore it is dif 1047297cult to pinpoint
a culprit drug in subsequent episodes considering cross- andpolysensitivity2 Verbov23 reported a case of FDE caused by
paracetamol-chlormezanone combination but not by either drug
alone Drug interactions may lead to formation of chemicals
causing FDE Although oral challenge with subtherapeutic dose
remains the most reliable method for de1047297ning the etiology it may
cause severe1047298are-upreactionsThus only patch tests were done on
the previously involved sites in this study
Because there is no clear de1047297nition of GBFDE in the literature
we proposed that it should ful1047297ll the description of typical FDE or
nonpigmented lesions and have at least bullae involving at least
three of the following different anatomic sites head and neck
(including the lips) anterior trunk back upper limbs lower
limbs and genitalia4e7 GBFDE is sometimes confused with SJS
TEN12
There have been reports of patients surviving from recur-rent TEN episodes but such cases are rare Some authors even
suspect that some of these cases are actually GBFDE rather than
TEN12
The present study shows that GBFDE patients are older than SJS
TEN patients and may have previous episodes Mucosal involve-
ment and constitutional symptoms are less frequent Commonly
incriminated drugs for bullous FDE are rifampicin metronidazole
paracetamol paclitaxel vinburnine erythromycin and ibuprofen3
This study showed antibiotics (three cases) are the most frequent
causative drugs in GBFDE Histopathologically FDE and SJSTEN
both showed basal vacuolization and dyskeratosis However the
presence of eosinophils neutrophils or melanophages in the
super1047297cial and deep in1047297ltrates favors GBFDE over SJSTEN12
The absence of 1047297
re 1047298
ag sign and higher eosinophil scores further
Figure 2 Pathologic features of toxic epidermal necrolysis (TEN) and generalized bullous 1047297xed drug eruption (GBFDE) (A B) TEN super1047297cial perivascular lymphocytic in1047298am-
mation aggregation of more than two dyskeratotic keratinocytes (1047297re 1047298ag sign arrows) and basal vacuolization (hematoxylin-eosin 40 and 100) (C) GBFDE discrete
dyskeratosis basal vacuolization and super1047297cial perivascular lymphocytic in1047298ammation (hematoxylin-eosin 100 (D) GBFDE pigment incontinence and eosinophils in the upper
dermis (hematoxylin-eosin 200)
C-H Lee et al Dermatologica Sinica 30 (2012) 11e1514
8102019 1e327b
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differentiate FDE from SJSTEN31112 Unfortunately because of the
limited number of cases further investigations are warranted
In conclusion NSAIDs and antibiotics are the most frequent
causative drugs of FDEs in Taiwan Patients with GBFDE are older
than non-GBFDE patients have more involvement of the trunk
and are easily misdiagnosed as TEN They are less likely to have
constitutional symptoms and mucosal involvement and may have
previous episodes Skin biopsy is important because the absence of
1047297re 1047298ag sign and eosinophils and melanophages in the super1047297cial
and deep in1047297ltration favors GBFDE Detailed histopathologic
examination from early stage lesions or perilesional skin along
with clinical information of previous episode constitutional
symptoms and mucosal involvement will be useful in differenti-
ating GBFDE from SJSTEN
Acknowledgments
The authors thank Yu-Hsian Tseng for her assistance in the statis-
tical computations
References
1 Ozkaya E Fixed drug eruption state of the art J Dtsch Dermatol Ges 20086181e8
2 Sehgal VN Srivastava G Fixed drug eruption (FDE) changing scenario of incriminating drugs Int J Dermatol 200645897e908
3 Wolff KGL Katz SI Gilchrest BA Paller AS Leffell DJ Fitzpatrickrsquo s dermatology in general medicine 7th ed New York McGraw-Hill 2008 359e360
4 Rai R Jain R Kaur I Kumar B Multifocal bullous 1047297xed drug eruptionmimicking Stevens-Johnson syndrome Indian J Dermatol Venereol Leprol 200268175e6
5 Shiohara T Mizukawa Y Fixed drug eruption a disease mediated by self-in1047298icted responses of intraepidermal T cells Eur J Dermatol 200717201e8
6 Mizukawa Y Shiohara T Nonpigmenting 1047297xed drug eruption as a possibleabortive variant of toxic epidermal necrolysis immunohistochemical andserum cytokine analyses Clin Exp Dermatol 201035493e7
7 Mockenhaupt M Severe drug-induced skin reactions clinical pattern diag-nostics and therapy J Dtsch Dermatol Ges 20097142e60
8 Long CC Finlay AY Marks R Fixed drug eruption to mefenamic acid a report of three cases Br J Dermatol 1992126409e11
9 Tanaka S Fixed drug eruption from piroxicam with positive lesional patch testContact Dermatitis 200246174
10 Auquier-Dunant A Mockenhaupt M Naldi L Correia O Schroder W Roujeau JC
Correlations between clinical patterns and causes of erythema multiformemajus Stevens-Johnson syndrome and toxic epidermal necrolysis results of an international prospective study Arch Dermatol 20021381019e24
11 Eduardo Calonje TB Lazar A McKee PH McKeersquo s pathology of the skin expert consult 4th ed 2012
12 Lin TK Hsu MM Lee JY Clinical resemblance of widespread bullous 1047297xed drugeruption to Stevens-Johnson syndrome or toxic epidermal necrolysis report of two cases J Formos Med Assoc 2002101572e6
13 Bourns D Unusual effects of antipyrine BMJ 18892818e2014 Brocq L Eruption erythemato-pigmentee 1047297xe due a Irsquoantipyrine Ann Dermatol
Venereol 18945308e1315 Shiohara T Fixed drug eruption pathogenesis and diagnostic tests Curr Opin
Allergy Clin Immunol 20099316e2116 Brahimi N Routier E Raison-Peyron N et al A three-year-analysis of 1047297xed drug
eruptions in hospital settings in France Eur J Dermatol 201020461e417 Patel RM Marfatia YS Clinical study of cutaneous drug eruptions in 200
patients Indian J Dermatol Venereol Leprol 20087443018 Chan HL Fixed drug eruptions A study of 20 occurrences in Singapore Int J
Dermatol 198423607e919 Mahboob A Haroon TS Drugs causing 1047297xed eruptions a study of 450 cases Int
J Dermatol 199837833e820 Ozkaya-Bayazit E Speci1047297c site involvement in 1047297xed drug eruption J Am Acad
Dermatol 2003491003e721 Gupta R Drugs causing 1047297xed drug eruptions con1047297rmed by provocation tests
Indian J Dermatol Venereol Leprol 200369120e122 Gruber F Stasic A Lenkovic M Brajac I Postcoital 1047297xed drug eruption in a man
sensitive to trimethoprim-sulphamethoxazole Clin Exp Dermatol 199722144e5
23 Verbov J Fixed drug eruption due to a drug combination but not to itsconstituents Dermatologica 198517160e1
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 15
8102019 1e327b
httpslidepdfcomreaderfull1e327b 25
brightred ordusky red macules that might evolve into an edematous
plaque with residual grayish or slate-colored hyperpigmentation
(Figure 1A)3 GBFDE was de1047297ned 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 consent89 Due to ethical
issues oral challenge tests were not performed Clinical data sus-
pected etiologies and pathologypatch test results were collected
from chart records Pathology-proved TEN or SJSTEN overlap
patients in the same period were included to compare with GBFDE
patients These TEN or SJSTEN overlap patients were diagnosed
according to the criteria proposed by the European Registry of
Severe Cutaneous Adverse Reactions (EuroSCAR) group10 Patho-
logic features such as super1047297cial or super1047297cial and deep in1047298am-
mation 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 speci1047297ed cell in the specimen score 1 lt 2
cells in every 400 high power 1047297eld (HPF) score 2 2e10 cells in
one HPF and score 3 gt 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
Fisherrsquos exact tests were conducted to compare differences in sex
frequency of previous events and lesion locations between the two
groups All of the statistical analyses were performed using the SAS
software (ver 913 SAS Institute Cary NC USA)
Results
FDE patients including GBFDE and non-GBFDE
Of the 39 FDE patients recruited in this study 30 were non-GBFDE
and nine were GBFDE cases (Table 1) The average age of FDE
patients was 522244 years (median 56 years range 4e86
years) The average and median ages of non-GBFDE were younger
than those of GBFDE (472 236 vs 691197 years pfrac1400124
and 46 vs 74 years) There was no signi1047297cant sex preference
although a trend of male predominance was noted (22 men and 17
women) A total of 20 of the 39 FDE patients (513) had previous
events including 14 (467) non-GBFDE and six (667) GBFDE
( pfrac1404506)
Fifteen FDE patients (385) had mucosal involvement GBFDE
cases seemed more likely to have mucosal lesions (667 vs non-
GBFDE 300 pfrac14 00631) GBFDE patients were also more likely
to have trunk involvement (889 in GBFDE vs400 in non-GBFDE pfrac1400197) These results are shown in Table 1
Etiologic agents
Nonsteroidal anti-in1047298ammatory drugs (NSAIDs) were the most
common causative agents accounting for 128 of cases (1047297ve cases
including four non-GBFDEand one GBFDE) Four cases (103) were
caused by antibiotics (one non-GBFDE and three GBFDE) Other
cases were caused by miscellaneous agents including computed
tomography contrast and unknown Chinese herbal drugs (Table 2)
During this period only 12 of the 39 patients received patch testing
of the suspected causative agents on the previous lesion sites four
(333) of whom had a positive reaction to the suspected drugs
GBFDE and TEN
Four TEN patients and two SJSTEN overlap patients were included
for comparison with GBFDE patients (Table 3) The GBFDE patients
were older than the SJSTEN overlap or TEN patients (691197 vs
587261 years median 74 vs 575 years) Previous events were
noted in six GBFDE patients (667) but none in the SJSTEN overlap
or TEN patients There was mucosal involvement in six GBFDE
Figure 1 (A) Fixed drug eruption round erythematous plaque with central dusky red
to grayish hyper-pigmentation (B) generalized bullous 1047297xed drug eruption large areas
of 1047298
accid blisters or erosions involving the abdomen thighs and glans penis
Table 1 Demographic data of patients with non-GBFDE and GBFDE
Total () Non-GBFDE () GBFDE () p value
Number 39 30 9 NA
Age (mean SD) y 522244 472236 691197 00124Median age 56 46 74 NA
Sex (WM) 1722 1416 36 07042
Previous events 20 (513) 14 (467) 6 (667) 04506
Location
Muco sal i nvo lve ment 15 (385) 9 (30 0) 6 ( 6667) 00631
Lip or oral mucosa 12 (308) 8 (267) 4 (444) 04161
Genital area 8 (205) 5 (1667) 3 (3333) 03548
Extremities
Hands 13 (333) 9 (300) 4 (444) 04472
Other extremi ti es 28 (718) 20 ( 667) 8 ( 8889) 03994
Trunk 20 (513) 12 (400) 8 (8889) 00197
Face 6 (154) 3 (100) 3 (333) 01225
Patch test (thorn) 48 35 13 NA
GBFDEfrac14 generalized bullous 1047297xed drug eruption NAfrac14 not applicable SDfrac14
standard deviation
C-H Lee et al Dermatologica Sinica 30 (2012) 11e1512
8102019 1e327b
httpslidepdfcomreaderfull1e327b 35
patients (667) and in all six SJSTEN overlap or TEN patients
Constitutional symptoms (eg fever chills or malaise) were more
common in SJSTEN overlap or TEN patients [three patients (50)
vs one in GBFDE (111)]To avoid examining secondary changes of skin pathology due to
blister formation or epidermal necrosis only biopsy specimens
taken from the perilesional skin or early stage lesions were used
for comparison of histopathologic features between GBFDE and
SJSTEN Seven and six histologic specimens were available for
evaluation in GBFDE and SJSTEN overlap or TEN patients respec-
tively The pathologic features of SJSTEN overlap or TEN specimens
showed super1047297cial perivascular in1047298ammation (100) basal
vacuolization (100) presence of 1047297re 1047298ag sign31112 (more than two
aggregated dyskeratotic keratinocytes 100) less pigment incon-
tinence (333) and lower eosinophil score (0e1) These results are
shown in Figure 2A and B
By contrast GBFDE specimens showed no aggregated dysker-
atotic keratinocytes in the epidermis (1047297re 1047298ag sign) (0) frequent
pigment incontinence (100) more common super1047297cial and deep
perivascular in1047298ammation (286) 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 SJSTEN
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 haveconstitutional symptoms than patients with SJSTEN overlap or
TEN The presence of eosinophils and pigment incontinence with
absent 1047297re 1047298ag sign is an important clue to differentiate GBFDE
from SJSTEN
Although the 1047297rst case of FDE was described by Bourns in
188913 the term FDE was 1047297rst proposed in 1894 by Brocq to
describe a special type of reaction to antipyrine14 The phenomenon
of lesions recurring at the previous involved sites has intrigued
many dermatologists Intraepidermal CD8thorn T cells with effector-
memory phenotype resident in FDE lesions are considered very
important in the disease pathogenesis FDE predisposing sites (ie
lips genital areas or hands) are frequent regions of herpes simplex
virus (HSV) reactivation15 Previous studies have found that the vast
majority of FDE patients are asymptomatic HSV seropositive indi-viduals and their anti-HSV immunoglobin G (IgG) titers are much
higher than in patients with HSV recurrences15 FDE lesions found
at previously traumatized sites such as burn scars and insect bites
were also well documented15 Moreover these T cells are found at
the site of repeated pathogen entry such as the lungs Thus
intraepidermal CD8thorn T cells with an effector-memory phenotype
resident in FDE lesions may mediate protective immunity15 Addi-
tional recruitment of other in1047298ammatory cells occurs in the late
stage of the disease and then disease activity is down regulated by
regulatory T cells15
A recent French study16 recruited 59 cases from 17 hospitals
over three years which indicate that FDE is not a common cuta-
neous adverse drug reaction (roughly one case per year per
hospital) However FDEs are the most frequent cutaneous reactions
Table 2 Suspected etiologies of FDE
Non-GBFDE (nfrac14 30) GBFDE (nfrac14 9) Total
NSAIDs 4 (mefenamic acidab sulindacab piroxicamab acemetacin) 1 (ibuprofenb) 5
Antibiotics 1 (cephalosporin) 3 (ceftriaxonea cefpiromeb tetracyclineb) 4
Other drugs 6 (rabeprazolebc levamisoleb allopurinolb propranolol Andrographis paniculatab
dicyclomine or mepenzolateb)
1 (allopurinolb) 7
Multiple drugs 7 [(doxycycline acetaminophenbc) (sulfamethoxazole and trimethoprim
diclofenacbc) (sulfamethoxazole and trimethoprim diclofenacbc) (clindamycin
sulfamethoxazole and trimethoprim ibuprofen pseudoephedrineb) (amoxicillinmefenamic acidb) (cephalexin levocetirizineb)(diclofenac indomethacin colchicin
allopurinolb)]
2 [(sulindac cimetidine calcium carbonatebc)
(amoxicillin hydroxyzine mefenamic acida)]
9
Other etiologies 5 [computed tomography contrast unknown Chinese herbal drugsb drug for headache
drugs for upper respiratory tract infection (two cases)]
0 5
Unknown 7 2 9
FDEfrac14 1047297xed-drug eruption GBFDEfrac14 generalized bullous 1047297xed drug eruption NSAIDfrac14nonsteroidal anti-in1047298ammatory druga Positive patch testb Previous events (thorn)c Negative patch test
Table 3 Comparison of clinical and pathologic features GBFDE and SJSTEN overlap
or TEN
GBFDE () SJSTEN overlap or TEN ()
Clinical features nfrac149 nfrac146
Average age (mean SD) y 691197 587261
Median age y 74 575
Sex (WM) 36 33
Previous events 6 (667) 0 (0)
Mucosal involvement 6 (667) 6 (100)
Con sti tuti onal symptoms 1 (111) 3 (50)
Pathologic features nfrac147 nfrac146
Perivascular in1047298ammation
Super1047297cial 5 (714) 6 (100)
Super1047297cial and deep 2 (286) 0 (0)
Basal vacuolization 7 (100) 6 (100)
Fire 1047298ag signa 0 (0) 6 (100)
Eosinophil scoreb
0 0 (0) 3 (50)
1 3 (429) 3 (50)
2 4 (571) 0 (0)
Neutrophil scoreb
0 6 (857) 4 (667)
1 0 (0) 2 (333)
2 1 (143) 0 (0)
Pigment incontinence 7 (100) 2 (333)
GBFDEfrac14 generalized bullous 1047297xed drug eruption HPFfrac14 high power 1047297eld NA not
applicable SDfrac14 standard deviation SJSfrac14 Stevens-Johnson syndrome TENfrac14 toxic
epidermal necrolysisa Fire 1047298ag sign more than two aggregated dyskeratotic keratinocytesb 0 no speci1047297ed cell in the specimen 1 speci1047297ed cell present but lt 2 cells in
every
400 HPF 2 2e
10 cells in one HPF 3gt
10 cells in one HPF
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 13
8102019 1e327b
httpslidepdfcomreaderfull1e327b 45
in one report from India accounting for 30 of all cutaneous
adverse drug reactions (61 cases over a 10-year study)17 There
werea total of 39 cases overan 11-year period in one referral center
for drug eruption and patch testing in northern Taiwan It seems
that the incidence rate of FDE in Taiwan is similar to that of IndiaThere may be some evidence of genetic predisposition to FDEs1
The average age of the patients in the current study is 522 years
which is older than those of previous reported series (around the
fourth decade)18e20 However the median age of one recent study
(58 years) is close to the present 1047297ndings16 The average age of
GBFDE patients is higher than those of non-GBFDE patients This
may be explained by the fact that GBFDE patients have more
previous episodes than non-GBFDE patients even though the
difference is not statistically signi1047297cant It is possible that some
patients may overlook or forget prior episodes
Some studies including the present one show a trend toward
a male predominance2 although female predominance has also
been reported16 In the present study extremities (not including
hands)(718) were the most frequently affected sites followed bytrunk (513) mucosa (385) and hands (333) In a study of site
involvement in FDE from 105 patients from Turkey genital mucosa
(505) was the most frequently involved site followed by the
trunk (381) lips (371) and hands (324)20 However some
studies show that the lips are the most frequently affected
site181921
The etiology of FDE varies depending on the drugs in vogue at
the time in different regions2 The list of causative drugs is long
including non-narcotic analgesics antibacterial agents antifungal
agents antipsychotics other miscellaneous drugs and even ultra-
violet radiation emotional and psychiatric factors heat menstrual
abnormalities pregnancy fatigue cold and undue effort2 There is
even one report describing a male patient with postcoital FDE after
his wife took the causative drug trimethoprimsulfamethoxazole
22
In the present study the etiologies are diverse It is very common
that patients take several drugs at one time and in this study nine
patients took multiple possible drugs Therefore it is dif 1047297cult to
identify the true etiology Furthermore it is dif 1047297cult to pinpoint
a culprit drug in subsequent episodes considering cross- andpolysensitivity2 Verbov23 reported a case of FDE caused by
paracetamol-chlormezanone combination but not by either drug
alone Drug interactions may lead to formation of chemicals
causing FDE Although oral challenge with subtherapeutic dose
remains the most reliable method for de1047297ning the etiology it may
cause severe1047298are-upreactionsThus only patch tests were done on
the previously involved sites in this study
Because there is no clear de1047297nition of GBFDE in the literature
we proposed that it should ful1047297ll the description of typical FDE or
nonpigmented lesions and have at least bullae involving at least
three of the following different anatomic sites head and neck
(including the lips) anterior trunk back upper limbs lower
limbs and genitalia4e7 GBFDE is sometimes confused with SJS
TEN12
There have been reports of patients surviving from recur-rent TEN episodes but such cases are rare Some authors even
suspect that some of these cases are actually GBFDE rather than
TEN12
The present study shows that GBFDE patients are older than SJS
TEN patients and may have previous episodes Mucosal involve-
ment and constitutional symptoms are less frequent Commonly
incriminated drugs for bullous FDE are rifampicin metronidazole
paracetamol paclitaxel vinburnine erythromycin and ibuprofen3
This study showed antibiotics (three cases) are the most frequent
causative drugs in GBFDE Histopathologically FDE and SJSTEN
both showed basal vacuolization and dyskeratosis However the
presence of eosinophils neutrophils or melanophages in the
super1047297cial and deep in1047297ltrates favors GBFDE over SJSTEN12
The absence of 1047297
re 1047298
ag sign and higher eosinophil scores further
Figure 2 Pathologic features of toxic epidermal necrolysis (TEN) and generalized bullous 1047297xed drug eruption (GBFDE) (A B) TEN super1047297cial perivascular lymphocytic in1047298am-
mation aggregation of more than two dyskeratotic keratinocytes (1047297re 1047298ag sign arrows) and basal vacuolization (hematoxylin-eosin 40 and 100) (C) GBFDE discrete
dyskeratosis basal vacuolization and super1047297cial perivascular lymphocytic in1047298ammation (hematoxylin-eosin 100 (D) GBFDE pigment incontinence and eosinophils in the upper
dermis (hematoxylin-eosin 200)
C-H Lee et al Dermatologica Sinica 30 (2012) 11e1514
8102019 1e327b
httpslidepdfcomreaderfull1e327b 55
differentiate FDE from SJSTEN31112 Unfortunately because of the
limited number of cases further investigations are warranted
In conclusion NSAIDs and antibiotics are the most frequent
causative drugs of FDEs in Taiwan Patients with GBFDE are older
than non-GBFDE patients have more involvement of the trunk
and are easily misdiagnosed as TEN They are less likely to have
constitutional symptoms and mucosal involvement and may have
previous episodes Skin biopsy is important because the absence of
1047297re 1047298ag sign and eosinophils and melanophages in the super1047297cial
and deep in1047297ltration favors GBFDE Detailed histopathologic
examination from early stage lesions or perilesional skin along
with clinical information of previous episode constitutional
symptoms and mucosal involvement will be useful in differenti-
ating GBFDE from SJSTEN
Acknowledgments
The authors thank Yu-Hsian Tseng for her assistance in the statis-
tical computations
References
1 Ozkaya E Fixed drug eruption state of the art J Dtsch Dermatol Ges 20086181e8
2 Sehgal VN Srivastava G Fixed drug eruption (FDE) changing scenario of incriminating drugs Int J Dermatol 200645897e908
3 Wolff KGL Katz SI Gilchrest BA Paller AS Leffell DJ Fitzpatrickrsquo s dermatology in general medicine 7th ed New York McGraw-Hill 2008 359e360
4 Rai R Jain R Kaur I Kumar B Multifocal bullous 1047297xed drug eruptionmimicking Stevens-Johnson syndrome Indian J Dermatol Venereol Leprol 200268175e6
5 Shiohara T Mizukawa Y Fixed drug eruption a disease mediated by self-in1047298icted responses of intraepidermal T cells Eur J Dermatol 200717201e8
6 Mizukawa Y Shiohara T Nonpigmenting 1047297xed drug eruption as a possibleabortive variant of toxic epidermal necrolysis immunohistochemical andserum cytokine analyses Clin Exp Dermatol 201035493e7
7 Mockenhaupt M Severe drug-induced skin reactions clinical pattern diag-nostics and therapy J Dtsch Dermatol Ges 20097142e60
8 Long CC Finlay AY Marks R Fixed drug eruption to mefenamic acid a report of three cases Br J Dermatol 1992126409e11
9 Tanaka S Fixed drug eruption from piroxicam with positive lesional patch testContact Dermatitis 200246174
10 Auquier-Dunant A Mockenhaupt M Naldi L Correia O Schroder W Roujeau JC
Correlations between clinical patterns and causes of erythema multiformemajus Stevens-Johnson syndrome and toxic epidermal necrolysis results of an international prospective study Arch Dermatol 20021381019e24
11 Eduardo Calonje TB Lazar A McKee PH McKeersquo s pathology of the skin expert consult 4th ed 2012
12 Lin TK Hsu MM Lee JY Clinical resemblance of widespread bullous 1047297xed drugeruption to Stevens-Johnson syndrome or toxic epidermal necrolysis report of two cases J Formos Med Assoc 2002101572e6
13 Bourns D Unusual effects of antipyrine BMJ 18892818e2014 Brocq L Eruption erythemato-pigmentee 1047297xe due a Irsquoantipyrine Ann Dermatol
Venereol 18945308e1315 Shiohara T Fixed drug eruption pathogenesis and diagnostic tests Curr Opin
Allergy Clin Immunol 20099316e2116 Brahimi N Routier E Raison-Peyron N et al A three-year-analysis of 1047297xed drug
eruptions in hospital settings in France Eur J Dermatol 201020461e417 Patel RM Marfatia YS Clinical study of cutaneous drug eruptions in 200
patients Indian J Dermatol Venereol Leprol 20087443018 Chan HL Fixed drug eruptions A study of 20 occurrences in Singapore Int J
Dermatol 198423607e919 Mahboob A Haroon TS Drugs causing 1047297xed eruptions a study of 450 cases Int
J Dermatol 199837833e820 Ozkaya-Bayazit E Speci1047297c site involvement in 1047297xed drug eruption J Am Acad
Dermatol 2003491003e721 Gupta R Drugs causing 1047297xed drug eruptions con1047297rmed by provocation tests
Indian J Dermatol Venereol Leprol 200369120e122 Gruber F Stasic A Lenkovic M Brajac I Postcoital 1047297xed drug eruption in a man
sensitive to trimethoprim-sulphamethoxazole Clin Exp Dermatol 199722144e5
23 Verbov J Fixed drug eruption due to a drug combination but not to itsconstituents Dermatologica 198517160e1
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 15
8102019 1e327b
httpslidepdfcomreaderfull1e327b 35
patients (667) and in all six SJSTEN overlap or TEN patients
Constitutional symptoms (eg fever chills or malaise) were more
common in SJSTEN overlap or TEN patients [three patients (50)
vs one in GBFDE (111)]To avoid examining secondary changes of skin pathology due to
blister formation or epidermal necrosis only biopsy specimens
taken from the perilesional skin or early stage lesions were used
for comparison of histopathologic features between GBFDE and
SJSTEN Seven and six histologic specimens were available for
evaluation in GBFDE and SJSTEN overlap or TEN patients respec-
tively The pathologic features of SJSTEN overlap or TEN specimens
showed super1047297cial perivascular in1047298ammation (100) basal
vacuolization (100) presence of 1047297re 1047298ag sign31112 (more than two
aggregated dyskeratotic keratinocytes 100) less pigment incon-
tinence (333) and lower eosinophil score (0e1) These results are
shown in Figure 2A and B
By contrast GBFDE specimens showed no aggregated dysker-
atotic keratinocytes in the epidermis (1047297re 1047298ag sign) (0) frequent
pigment incontinence (100) more common super1047297cial and deep
perivascular in1047298ammation (286) 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 SJSTEN
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 haveconstitutional symptoms than patients with SJSTEN overlap or
TEN The presence of eosinophils and pigment incontinence with
absent 1047297re 1047298ag sign is an important clue to differentiate GBFDE
from SJSTEN
Although the 1047297rst case of FDE was described by Bourns in
188913 the term FDE was 1047297rst proposed in 1894 by Brocq to
describe a special type of reaction to antipyrine14 The phenomenon
of lesions recurring at the previous involved sites has intrigued
many dermatologists Intraepidermal CD8thorn T cells with effector-
memory phenotype resident in FDE lesions are considered very
important in the disease pathogenesis FDE predisposing sites (ie
lips genital areas or hands) are frequent regions of herpes simplex
virus (HSV) reactivation15 Previous studies have found that the vast
majority of FDE patients are asymptomatic HSV seropositive indi-viduals and their anti-HSV immunoglobin G (IgG) titers are much
higher than in patients with HSV recurrences15 FDE lesions found
at previously traumatized sites such as burn scars and insect bites
were also well documented15 Moreover these T cells are found at
the site of repeated pathogen entry such as the lungs Thus
intraepidermal CD8thorn T cells with an effector-memory phenotype
resident in FDE lesions may mediate protective immunity15 Addi-
tional recruitment of other in1047298ammatory cells occurs in the late
stage of the disease and then disease activity is down regulated by
regulatory T cells15
A recent French study16 recruited 59 cases from 17 hospitals
over three years which indicate that FDE is not a common cuta-
neous adverse drug reaction (roughly one case per year per
hospital) However FDEs are the most frequent cutaneous reactions
Table 2 Suspected etiologies of FDE
Non-GBFDE (nfrac14 30) GBFDE (nfrac14 9) Total
NSAIDs 4 (mefenamic acidab sulindacab piroxicamab acemetacin) 1 (ibuprofenb) 5
Antibiotics 1 (cephalosporin) 3 (ceftriaxonea cefpiromeb tetracyclineb) 4
Other drugs 6 (rabeprazolebc levamisoleb allopurinolb propranolol Andrographis paniculatab
dicyclomine or mepenzolateb)
1 (allopurinolb) 7
Multiple drugs 7 [(doxycycline acetaminophenbc) (sulfamethoxazole and trimethoprim
diclofenacbc) (sulfamethoxazole and trimethoprim diclofenacbc) (clindamycin
sulfamethoxazole and trimethoprim ibuprofen pseudoephedrineb) (amoxicillinmefenamic acidb) (cephalexin levocetirizineb)(diclofenac indomethacin colchicin
allopurinolb)]
2 [(sulindac cimetidine calcium carbonatebc)
(amoxicillin hydroxyzine mefenamic acida)]
9
Other etiologies 5 [computed tomography contrast unknown Chinese herbal drugsb drug for headache
drugs for upper respiratory tract infection (two cases)]
0 5
Unknown 7 2 9
FDEfrac14 1047297xed-drug eruption GBFDEfrac14 generalized bullous 1047297xed drug eruption NSAIDfrac14nonsteroidal anti-in1047298ammatory druga Positive patch testb Previous events (thorn)c Negative patch test
Table 3 Comparison of clinical and pathologic features GBFDE and SJSTEN overlap
or TEN
GBFDE () SJSTEN overlap or TEN ()
Clinical features nfrac149 nfrac146
Average age (mean SD) y 691197 587261
Median age y 74 575
Sex (WM) 36 33
Previous events 6 (667) 0 (0)
Mucosal involvement 6 (667) 6 (100)
Con sti tuti onal symptoms 1 (111) 3 (50)
Pathologic features nfrac147 nfrac146
Perivascular in1047298ammation
Super1047297cial 5 (714) 6 (100)
Super1047297cial and deep 2 (286) 0 (0)
Basal vacuolization 7 (100) 6 (100)
Fire 1047298ag signa 0 (0) 6 (100)
Eosinophil scoreb
0 0 (0) 3 (50)
1 3 (429) 3 (50)
2 4 (571) 0 (0)
Neutrophil scoreb
0 6 (857) 4 (667)
1 0 (0) 2 (333)
2 1 (143) 0 (0)
Pigment incontinence 7 (100) 2 (333)
GBFDEfrac14 generalized bullous 1047297xed drug eruption HPFfrac14 high power 1047297eld NA not
applicable SDfrac14 standard deviation SJSfrac14 Stevens-Johnson syndrome TENfrac14 toxic
epidermal necrolysisa Fire 1047298ag sign more than two aggregated dyskeratotic keratinocytesb 0 no speci1047297ed cell in the specimen 1 speci1047297ed cell present but lt 2 cells in
every
400 HPF 2 2e
10 cells in one HPF 3gt
10 cells in one HPF
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 13
8102019 1e327b
httpslidepdfcomreaderfull1e327b 45
in one report from India accounting for 30 of all cutaneous
adverse drug reactions (61 cases over a 10-year study)17 There
werea total of 39 cases overan 11-year period in one referral center
for drug eruption and patch testing in northern Taiwan It seems
that the incidence rate of FDE in Taiwan is similar to that of IndiaThere may be some evidence of genetic predisposition to FDEs1
The average age of the patients in the current study is 522 years
which is older than those of previous reported series (around the
fourth decade)18e20 However the median age of one recent study
(58 years) is close to the present 1047297ndings16 The average age of
GBFDE patients is higher than those of non-GBFDE patients This
may be explained by the fact that GBFDE patients have more
previous episodes than non-GBFDE patients even though the
difference is not statistically signi1047297cant It is possible that some
patients may overlook or forget prior episodes
Some studies including the present one show a trend toward
a male predominance2 although female predominance has also
been reported16 In the present study extremities (not including
hands)(718) were the most frequently affected sites followed bytrunk (513) mucosa (385) and hands (333) In a study of site
involvement in FDE from 105 patients from Turkey genital mucosa
(505) was the most frequently involved site followed by the
trunk (381) lips (371) and hands (324)20 However some
studies show that the lips are the most frequently affected
site181921
The etiology of FDE varies depending on the drugs in vogue at
the time in different regions2 The list of causative drugs is long
including non-narcotic analgesics antibacterial agents antifungal
agents antipsychotics other miscellaneous drugs and even ultra-
violet radiation emotional and psychiatric factors heat menstrual
abnormalities pregnancy fatigue cold and undue effort2 There is
even one report describing a male patient with postcoital FDE after
his wife took the causative drug trimethoprimsulfamethoxazole
22
In the present study the etiologies are diverse It is very common
that patients take several drugs at one time and in this study nine
patients took multiple possible drugs Therefore it is dif 1047297cult to
identify the true etiology Furthermore it is dif 1047297cult to pinpoint
a culprit drug in subsequent episodes considering cross- andpolysensitivity2 Verbov23 reported a case of FDE caused by
paracetamol-chlormezanone combination but not by either drug
alone Drug interactions may lead to formation of chemicals
causing FDE Although oral challenge with subtherapeutic dose
remains the most reliable method for de1047297ning the etiology it may
cause severe1047298are-upreactionsThus only patch tests were done on
the previously involved sites in this study
Because there is no clear de1047297nition of GBFDE in the literature
we proposed that it should ful1047297ll the description of typical FDE or
nonpigmented lesions and have at least bullae involving at least
three of the following different anatomic sites head and neck
(including the lips) anterior trunk back upper limbs lower
limbs and genitalia4e7 GBFDE is sometimes confused with SJS
TEN12
There have been reports of patients surviving from recur-rent TEN episodes but such cases are rare Some authors even
suspect that some of these cases are actually GBFDE rather than
TEN12
The present study shows that GBFDE patients are older than SJS
TEN patients and may have previous episodes Mucosal involve-
ment and constitutional symptoms are less frequent Commonly
incriminated drugs for bullous FDE are rifampicin metronidazole
paracetamol paclitaxel vinburnine erythromycin and ibuprofen3
This study showed antibiotics (three cases) are the most frequent
causative drugs in GBFDE Histopathologically FDE and SJSTEN
both showed basal vacuolization and dyskeratosis However the
presence of eosinophils neutrophils or melanophages in the
super1047297cial and deep in1047297ltrates favors GBFDE over SJSTEN12
The absence of 1047297
re 1047298
ag sign and higher eosinophil scores further
Figure 2 Pathologic features of toxic epidermal necrolysis (TEN) and generalized bullous 1047297xed drug eruption (GBFDE) (A B) TEN super1047297cial perivascular lymphocytic in1047298am-
mation aggregation of more than two dyskeratotic keratinocytes (1047297re 1047298ag sign arrows) and basal vacuolization (hematoxylin-eosin 40 and 100) (C) GBFDE discrete
dyskeratosis basal vacuolization and super1047297cial perivascular lymphocytic in1047298ammation (hematoxylin-eosin 100 (D) GBFDE pigment incontinence and eosinophils in the upper
dermis (hematoxylin-eosin 200)
C-H Lee et al Dermatologica Sinica 30 (2012) 11e1514
8102019 1e327b
httpslidepdfcomreaderfull1e327b 55
differentiate FDE from SJSTEN31112 Unfortunately because of the
limited number of cases further investigations are warranted
In conclusion NSAIDs and antibiotics are the most frequent
causative drugs of FDEs in Taiwan Patients with GBFDE are older
than non-GBFDE patients have more involvement of the trunk
and are easily misdiagnosed as TEN They are less likely to have
constitutional symptoms and mucosal involvement and may have
previous episodes Skin biopsy is important because the absence of
1047297re 1047298ag sign and eosinophils and melanophages in the super1047297cial
and deep in1047297ltration favors GBFDE Detailed histopathologic
examination from early stage lesions or perilesional skin along
with clinical information of previous episode constitutional
symptoms and mucosal involvement will be useful in differenti-
ating GBFDE from SJSTEN
Acknowledgments
The authors thank Yu-Hsian Tseng for her assistance in the statis-
tical computations
References
1 Ozkaya E Fixed drug eruption state of the art J Dtsch Dermatol Ges 20086181e8
2 Sehgal VN Srivastava G Fixed drug eruption (FDE) changing scenario of incriminating drugs Int J Dermatol 200645897e908
3 Wolff KGL Katz SI Gilchrest BA Paller AS Leffell DJ Fitzpatrickrsquo s dermatology in general medicine 7th ed New York McGraw-Hill 2008 359e360
4 Rai R Jain R Kaur I Kumar B Multifocal bullous 1047297xed drug eruptionmimicking Stevens-Johnson syndrome Indian J Dermatol Venereol Leprol 200268175e6
5 Shiohara T Mizukawa Y Fixed drug eruption a disease mediated by self-in1047298icted responses of intraepidermal T cells Eur J Dermatol 200717201e8
6 Mizukawa Y Shiohara T Nonpigmenting 1047297xed drug eruption as a possibleabortive variant of toxic epidermal necrolysis immunohistochemical andserum cytokine analyses Clin Exp Dermatol 201035493e7
7 Mockenhaupt M Severe drug-induced skin reactions clinical pattern diag-nostics and therapy J Dtsch Dermatol Ges 20097142e60
8 Long CC Finlay AY Marks R Fixed drug eruption to mefenamic acid a report of three cases Br J Dermatol 1992126409e11
9 Tanaka S Fixed drug eruption from piroxicam with positive lesional patch testContact Dermatitis 200246174
10 Auquier-Dunant A Mockenhaupt M Naldi L Correia O Schroder W Roujeau JC
Correlations between clinical patterns and causes of erythema multiformemajus Stevens-Johnson syndrome and toxic epidermal necrolysis results of an international prospective study Arch Dermatol 20021381019e24
11 Eduardo Calonje TB Lazar A McKee PH McKeersquo s pathology of the skin expert consult 4th ed 2012
12 Lin TK Hsu MM Lee JY Clinical resemblance of widespread bullous 1047297xed drugeruption to Stevens-Johnson syndrome or toxic epidermal necrolysis report of two cases J Formos Med Assoc 2002101572e6
13 Bourns D Unusual effects of antipyrine BMJ 18892818e2014 Brocq L Eruption erythemato-pigmentee 1047297xe due a Irsquoantipyrine Ann Dermatol
Venereol 18945308e1315 Shiohara T Fixed drug eruption pathogenesis and diagnostic tests Curr Opin
Allergy Clin Immunol 20099316e2116 Brahimi N Routier E Raison-Peyron N et al A three-year-analysis of 1047297xed drug
eruptions in hospital settings in France Eur J Dermatol 201020461e417 Patel RM Marfatia YS Clinical study of cutaneous drug eruptions in 200
patients Indian J Dermatol Venereol Leprol 20087443018 Chan HL Fixed drug eruptions A study of 20 occurrences in Singapore Int J
Dermatol 198423607e919 Mahboob A Haroon TS Drugs causing 1047297xed eruptions a study of 450 cases Int
J Dermatol 199837833e820 Ozkaya-Bayazit E Speci1047297c site involvement in 1047297xed drug eruption J Am Acad
Dermatol 2003491003e721 Gupta R Drugs causing 1047297xed drug eruptions con1047297rmed by provocation tests
Indian J Dermatol Venereol Leprol 200369120e122 Gruber F Stasic A Lenkovic M Brajac I Postcoital 1047297xed drug eruption in a man
sensitive to trimethoprim-sulphamethoxazole Clin Exp Dermatol 199722144e5
23 Verbov J Fixed drug eruption due to a drug combination but not to itsconstituents Dermatologica 198517160e1
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 15
8102019 1e327b
httpslidepdfcomreaderfull1e327b 45
in one report from India accounting for 30 of all cutaneous
adverse drug reactions (61 cases over a 10-year study)17 There
werea total of 39 cases overan 11-year period in one referral center
for drug eruption and patch testing in northern Taiwan It seems
that the incidence rate of FDE in Taiwan is similar to that of IndiaThere may be some evidence of genetic predisposition to FDEs1
The average age of the patients in the current study is 522 years
which is older than those of previous reported series (around the
fourth decade)18e20 However the median age of one recent study
(58 years) is close to the present 1047297ndings16 The average age of
GBFDE patients is higher than those of non-GBFDE patients This
may be explained by the fact that GBFDE patients have more
previous episodes than non-GBFDE patients even though the
difference is not statistically signi1047297cant It is possible that some
patients may overlook or forget prior episodes
Some studies including the present one show a trend toward
a male predominance2 although female predominance has also
been reported16 In the present study extremities (not including
hands)(718) were the most frequently affected sites followed bytrunk (513) mucosa (385) and hands (333) In a study of site
involvement in FDE from 105 patients from Turkey genital mucosa
(505) was the most frequently involved site followed by the
trunk (381) lips (371) and hands (324)20 However some
studies show that the lips are the most frequently affected
site181921
The etiology of FDE varies depending on the drugs in vogue at
the time in different regions2 The list of causative drugs is long
including non-narcotic analgesics antibacterial agents antifungal
agents antipsychotics other miscellaneous drugs and even ultra-
violet radiation emotional and psychiatric factors heat menstrual
abnormalities pregnancy fatigue cold and undue effort2 There is
even one report describing a male patient with postcoital FDE after
his wife took the causative drug trimethoprimsulfamethoxazole
22
In the present study the etiologies are diverse It is very common
that patients take several drugs at one time and in this study nine
patients took multiple possible drugs Therefore it is dif 1047297cult to
identify the true etiology Furthermore it is dif 1047297cult to pinpoint
a culprit drug in subsequent episodes considering cross- andpolysensitivity2 Verbov23 reported a case of FDE caused by
paracetamol-chlormezanone combination but not by either drug
alone Drug interactions may lead to formation of chemicals
causing FDE Although oral challenge with subtherapeutic dose
remains the most reliable method for de1047297ning the etiology it may
cause severe1047298are-upreactionsThus only patch tests were done on
the previously involved sites in this study
Because there is no clear de1047297nition of GBFDE in the literature
we proposed that it should ful1047297ll the description of typical FDE or
nonpigmented lesions and have at least bullae involving at least
three of the following different anatomic sites head and neck
(including the lips) anterior trunk back upper limbs lower
limbs and genitalia4e7 GBFDE is sometimes confused with SJS
TEN12
There have been reports of patients surviving from recur-rent TEN episodes but such cases are rare Some authors even
suspect that some of these cases are actually GBFDE rather than
TEN12
The present study shows that GBFDE patients are older than SJS
TEN patients and may have previous episodes Mucosal involve-
ment and constitutional symptoms are less frequent Commonly
incriminated drugs for bullous FDE are rifampicin metronidazole
paracetamol paclitaxel vinburnine erythromycin and ibuprofen3
This study showed antibiotics (three cases) are the most frequent
causative drugs in GBFDE Histopathologically FDE and SJSTEN
both showed basal vacuolization and dyskeratosis However the
presence of eosinophils neutrophils or melanophages in the
super1047297cial and deep in1047297ltrates favors GBFDE over SJSTEN12
The absence of 1047297
re 1047298
ag sign and higher eosinophil scores further
Figure 2 Pathologic features of toxic epidermal necrolysis (TEN) and generalized bullous 1047297xed drug eruption (GBFDE) (A B) TEN super1047297cial perivascular lymphocytic in1047298am-
mation aggregation of more than two dyskeratotic keratinocytes (1047297re 1047298ag sign arrows) and basal vacuolization (hematoxylin-eosin 40 and 100) (C) GBFDE discrete
dyskeratosis basal vacuolization and super1047297cial perivascular lymphocytic in1047298ammation (hematoxylin-eosin 100 (D) GBFDE pigment incontinence and eosinophils in the upper
dermis (hematoxylin-eosin 200)
C-H Lee et al Dermatologica Sinica 30 (2012) 11e1514
8102019 1e327b
httpslidepdfcomreaderfull1e327b 55
differentiate FDE from SJSTEN31112 Unfortunately because of the
limited number of cases further investigations are warranted
In conclusion NSAIDs and antibiotics are the most frequent
causative drugs of FDEs in Taiwan Patients with GBFDE are older
than non-GBFDE patients have more involvement of the trunk
and are easily misdiagnosed as TEN They are less likely to have
constitutional symptoms and mucosal involvement and may have
previous episodes Skin biopsy is important because the absence of
1047297re 1047298ag sign and eosinophils and melanophages in the super1047297cial
and deep in1047297ltration favors GBFDE Detailed histopathologic
examination from early stage lesions or perilesional skin along
with clinical information of previous episode constitutional
symptoms and mucosal involvement will be useful in differenti-
ating GBFDE from SJSTEN
Acknowledgments
The authors thank Yu-Hsian Tseng for her assistance in the statis-
tical computations
References
1 Ozkaya E Fixed drug eruption state of the art J Dtsch Dermatol Ges 20086181e8
2 Sehgal VN Srivastava G Fixed drug eruption (FDE) changing scenario of incriminating drugs Int J Dermatol 200645897e908
3 Wolff KGL Katz SI Gilchrest BA Paller AS Leffell DJ Fitzpatrickrsquo s dermatology in general medicine 7th ed New York McGraw-Hill 2008 359e360
4 Rai R Jain R Kaur I Kumar B Multifocal bullous 1047297xed drug eruptionmimicking Stevens-Johnson syndrome Indian J Dermatol Venereol Leprol 200268175e6
5 Shiohara T Mizukawa Y Fixed drug eruption a disease mediated by self-in1047298icted responses of intraepidermal T cells Eur J Dermatol 200717201e8
6 Mizukawa Y Shiohara T Nonpigmenting 1047297xed drug eruption as a possibleabortive variant of toxic epidermal necrolysis immunohistochemical andserum cytokine analyses Clin Exp Dermatol 201035493e7
7 Mockenhaupt M Severe drug-induced skin reactions clinical pattern diag-nostics and therapy J Dtsch Dermatol Ges 20097142e60
8 Long CC Finlay AY Marks R Fixed drug eruption to mefenamic acid a report of three cases Br J Dermatol 1992126409e11
9 Tanaka S Fixed drug eruption from piroxicam with positive lesional patch testContact Dermatitis 200246174
10 Auquier-Dunant A Mockenhaupt M Naldi L Correia O Schroder W Roujeau JC
Correlations between clinical patterns and causes of erythema multiformemajus Stevens-Johnson syndrome and toxic epidermal necrolysis results of an international prospective study Arch Dermatol 20021381019e24
11 Eduardo Calonje TB Lazar A McKee PH McKeersquo s pathology of the skin expert consult 4th ed 2012
12 Lin TK Hsu MM Lee JY Clinical resemblance of widespread bullous 1047297xed drugeruption to Stevens-Johnson syndrome or toxic epidermal necrolysis report of two cases J Formos Med Assoc 2002101572e6
13 Bourns D Unusual effects of antipyrine BMJ 18892818e2014 Brocq L Eruption erythemato-pigmentee 1047297xe due a Irsquoantipyrine Ann Dermatol
Venereol 18945308e1315 Shiohara T Fixed drug eruption pathogenesis and diagnostic tests Curr Opin
Allergy Clin Immunol 20099316e2116 Brahimi N Routier E Raison-Peyron N et al A three-year-analysis of 1047297xed drug
eruptions in hospital settings in France Eur J Dermatol 201020461e417 Patel RM Marfatia YS Clinical study of cutaneous drug eruptions in 200
patients Indian J Dermatol Venereol Leprol 20087443018 Chan HL Fixed drug eruptions A study of 20 occurrences in Singapore Int J
Dermatol 198423607e919 Mahboob A Haroon TS Drugs causing 1047297xed eruptions a study of 450 cases Int
J Dermatol 199837833e820 Ozkaya-Bayazit E Speci1047297c site involvement in 1047297xed drug eruption J Am Acad
Dermatol 2003491003e721 Gupta R Drugs causing 1047297xed drug eruptions con1047297rmed by provocation tests
Indian J Dermatol Venereol Leprol 200369120e122 Gruber F Stasic A Lenkovic M Brajac I Postcoital 1047297xed drug eruption in a man
sensitive to trimethoprim-sulphamethoxazole Clin Exp Dermatol 199722144e5
23 Verbov J Fixed drug eruption due to a drug combination but not to itsconstituents Dermatologica 198517160e1
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 15
8102019 1e327b
httpslidepdfcomreaderfull1e327b 55
differentiate FDE from SJSTEN31112 Unfortunately because of the
limited number of cases further investigations are warranted
In conclusion NSAIDs and antibiotics are the most frequent
causative drugs of FDEs in Taiwan Patients with GBFDE are older
than non-GBFDE patients have more involvement of the trunk
and are easily misdiagnosed as TEN They are less likely to have
constitutional symptoms and mucosal involvement and may have
previous episodes Skin biopsy is important because the absence of
1047297re 1047298ag sign and eosinophils and melanophages in the super1047297cial
and deep in1047297ltration favors GBFDE Detailed histopathologic
examination from early stage lesions or perilesional skin along
with clinical information of previous episode constitutional
symptoms and mucosal involvement will be useful in differenti-
ating GBFDE from SJSTEN
Acknowledgments
The authors thank Yu-Hsian Tseng for her assistance in the statis-
tical computations
References
1 Ozkaya E Fixed drug eruption state of the art J Dtsch Dermatol Ges 20086181e8
2 Sehgal VN Srivastava G Fixed drug eruption (FDE) changing scenario of incriminating drugs Int J Dermatol 200645897e908
3 Wolff KGL Katz SI Gilchrest BA Paller AS Leffell DJ Fitzpatrickrsquo s dermatology in general medicine 7th ed New York McGraw-Hill 2008 359e360
4 Rai R Jain R Kaur I Kumar B Multifocal bullous 1047297xed drug eruptionmimicking Stevens-Johnson syndrome Indian J Dermatol Venereol Leprol 200268175e6
5 Shiohara T Mizukawa Y Fixed drug eruption a disease mediated by self-in1047298icted responses of intraepidermal T cells Eur J Dermatol 200717201e8
6 Mizukawa Y Shiohara T Nonpigmenting 1047297xed drug eruption as a possibleabortive variant of toxic epidermal necrolysis immunohistochemical andserum cytokine analyses Clin Exp Dermatol 201035493e7
7 Mockenhaupt M Severe drug-induced skin reactions clinical pattern diag-nostics and therapy J Dtsch Dermatol Ges 20097142e60
8 Long CC Finlay AY Marks R Fixed drug eruption to mefenamic acid a report of three cases Br J Dermatol 1992126409e11
9 Tanaka S Fixed drug eruption from piroxicam with positive lesional patch testContact Dermatitis 200246174
10 Auquier-Dunant A Mockenhaupt M Naldi L Correia O Schroder W Roujeau JC
Correlations between clinical patterns and causes of erythema multiformemajus Stevens-Johnson syndrome and toxic epidermal necrolysis results of an international prospective study Arch Dermatol 20021381019e24
11 Eduardo Calonje TB Lazar A McKee PH McKeersquo s pathology of the skin expert consult 4th ed 2012
12 Lin TK Hsu MM Lee JY Clinical resemblance of widespread bullous 1047297xed drugeruption to Stevens-Johnson syndrome or toxic epidermal necrolysis report of two cases J Formos Med Assoc 2002101572e6
13 Bourns D Unusual effects of antipyrine BMJ 18892818e2014 Brocq L Eruption erythemato-pigmentee 1047297xe due a Irsquoantipyrine Ann Dermatol
Venereol 18945308e1315 Shiohara T Fixed drug eruption pathogenesis and diagnostic tests Curr Opin
Allergy Clin Immunol 20099316e2116 Brahimi N Routier E Raison-Peyron N et al A three-year-analysis of 1047297xed drug
eruptions in hospital settings in France Eur J Dermatol 201020461e417 Patel RM Marfatia YS Clinical study of cutaneous drug eruptions in 200
patients Indian J Dermatol Venereol Leprol 20087443018 Chan HL Fixed drug eruptions A study of 20 occurrences in Singapore Int J
Dermatol 198423607e919 Mahboob A Haroon TS Drugs causing 1047297xed eruptions a study of 450 cases Int
J Dermatol 199837833e820 Ozkaya-Bayazit E Speci1047297c site involvement in 1047297xed drug eruption J Am Acad
Dermatol 2003491003e721 Gupta R Drugs causing 1047297xed drug eruptions con1047297rmed by provocation tests
Indian J Dermatol Venereol Leprol 200369120e122 Gruber F Stasic A Lenkovic M Brajac I Postcoital 1047297xed drug eruption in a man
sensitive to trimethoprim-sulphamethoxazole Clin Exp Dermatol 199722144e5
23 Verbov J Fixed drug eruption due to a drug combination but not to itsconstituents Dermatologica 198517160e1
C-H Lee et al Dermatologica Sinica 30 (2012) 11e15 15
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