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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


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


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


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)


8102019 1e327b


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


8102019 1e327b


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


8102019 1e327b

























Discussion









from SJSTEN






























1 (allopurinolb) 7




allopurinolb)]



9



0 5

Unknown 7 2 9



or TEN




Median age y 74 575

Sex (WM) 36 33






Super1047297cial 5 (714) 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)





every

400 HPF 2 2e


10 cells in one HPF


8102019 1e327b
























site181921









22


















TEN12



TEN12












re 1047298







8102019 1e327b
















Acknowledgments


tical computations

References


























8102019 1e327b

























Discussion









from SJSTEN






























1 (allopurinolb) 7




allopurinolb)]



9



0 5

Unknown 7 2 9



or TEN




Median age y 74 575

Sex (WM) 36 33






Super1047297cial 5 (714) 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)





every

400 HPF 2 2e


10 cells in one HPF


8102019 1e327b
























site181921









22


















TEN12



TEN12












re 1047298







8102019 1e327b
















Acknowledgments


tical computations

References


























8102019 1e327b
























site181921









22


















TEN12



TEN12












re 1047298







8102019 1e327b
















Acknowledgments


tical computations

References


























8102019 1e327b
















Acknowledgments


tical computations

References


























Documents

1e327b