Pharmacology and therapeutics

Occupational toxic epidermal necrolysis associated with

dalbergia cochinchinensis: a retrospective comparative study
of eight cases in China
Yongsheng Yang, MSc, Zhen Zhang, MSc, Xiaonian Lu, MD, Xiaohua Zhu, MD,
Qiong Huang, MD, Jun Liang, MD, and Jinhua Xu, MD

Affiliated Huashan Hospital, Fudan Abstract

University, Shanghai, China Background Occupational toxic epidermal necrolysis (TEN) related to Dalbergia
cochinchinensis has seldom been reported in the past. Its clinical characteristic needs to
Correspondence
Jinhua Xu, MD
be investigated. This study reports eight cases of such disease in China.
Department of Dermatology Methods Eight patients with occupational TEN admitted from 2003 to 2012 were
Affiliated Huashan Hospital retrospectively analyzed and compared with 15 patients admitted with TEN caused by
Fudan University drugs as controls. Patients all received combination therapy of corticosteroid and
Shanghai 200040
intravenous immunoglobulin. The times for bullous ceasing, tapering of corticosteroid, and
China
total hospitalization were compared between the two groups of patients. SCORTEN, a
E-mail: yangyongsheng73512@126.com
severity-of-illness scoring system for TEN prognosis, was applied to evaluate clinical
Conflicts of interest: None. outcome.
Results The three time measurements in occupational TEN were longer than those in
control, and the differences were statistically significant (P = 0.0023, 0.026, 0.0017), which
means the total dose of corticosteroid needed in occupational TEN was higher than that in
the control. There were no deaths in the two groups, although expected deaths were 0.612
and 0.836, respectively.
Discussion Occupational TEN has a longer progression than TEN caused by drugs, and
there is more difficulty in its treatment. Clinicians should pay attention to this disease.
However, its mechanism and target therapy remain unclear.

bicarbonate, and glucose. A low score (i.e., 0–1) corre-

Introduction
Toxic epidermal necrolysis (TEN) is a life-threatening
disease characterized by widespread epidermal sloughing
of skin accompanied by mucous membrane involvement.
There is growing evidence that Stevens–Johnson syn-
drome (SJS) and TEN are a single disease with common
causes and mechanisms, but the principal difference is the
extent of detachment, limited in SJS and more widespread
(more than 30% of the total body surface) in TEN. The
vast majority of TEN is caused by drugs. Other medica-
tion-related factors that have been hypothesized to induce
TEN include HIV, radiotherapy, and lupus erythemato-
sus.1 Furthermore, there are some rare cases caused by
occupational exposure to chemicals such as dendrimers,
thiourea dioxide, and ultraviolet-cured inks.2–4
Currently, the SCORTEN is a validated measure of the
disease severity that accurately predicts mortality using a
seven-point checklist including age, presence of malig-
nancy, body surface area involved, heart rate, serum urea,
sponds to a 3.2% mortality rate, and a high score (≥5)
corresponds to a 90% mortality rate.5 However, there is
no standardized treatment applicable for all patients with
TEN. A trend for a beneficial effect of combination ther-
apy of intravenous immunoglobulin (IVIG) and cortico-
steroid was noted in our previous study based on the
SCORTEN system.6 This combination therapy has rou-
tinely been applied in our department together with sup-
portive therapy, including fluid compensation, electrolyte
balancing, nutritional support, and local management, as
well as intensive care handling.
From 2003 to 2012, eight furniture factory workers
who developed TEN after contacting Dalbergia cochin-
chinensis were admitted. They presented the same clinical
manifestation, and their diagnoses were confirmed by skin
biopsy. However, whether this kind of TEN is different
from the others caused by drugs needs to be investigated
regarding its clinical course and response to the current
treatment. 1435

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1436 Pharmacology and therapeutics Occupational toxic epidermal necrolysis
Method
There were eight cases of TEN in the study group. Patients were
all previously healthy (without organ medical history or a history
of malignancy), aged 28–46 years old. During three months
before admission, they had no history of drug intake, and there
were no complications of herpes simplex or other infectious
diseases on admission. In addition, they had not received high-
dose corticosteroid (equivalent to prednisone >1 mg/kg per day)
therapy after onset of disease. Their SCORTEN scores ranged
from 1 to 2 (listed in Table 1). To match their clinical features
and to avoid heterogeneity, drug-induced TEN as the control
needed to fulfill the following inclusion criteria: (i) without liver,
kidney, or any other organ medical history; (ii) without high-dose
corticosteroid therapy after onset of disease before admission;
(iii) without a history of malignancy; (iv) age 20–50 years old; (v)
without infectious diseases on admission; (vi) SCORTEN scores
ranged from 1 to 2.
All patients in the study group and control group were treated
with the same combination therapy of IVIG and corticosteroid,
together with supportive therapy and local management.
Methylprednisolone was usually administered with an initial
dose in the range 1–1.5 mg/kg per day (or other equivalent
corticosteroids). A total dose of 2 g/kg of IVIG was also applied
(dose of 0.4 g/kg per day of IVIG for five consecutive days).
Skin biopsies were performed on the first day of admission to
confirm the diagnosis; histological evaluations were determined
by three pathologists with consistent opinion.
Overall survival and time to remission or response (in terms
of time to arrest of progression, time to tapering of
corticosteroid, time of hospitalization) were considered as
endpoints in our study. The evaluations were determined by a
group of dermatologists; they evaluated the condition of each
patient daily according to the clinical manifestation and sign as
well as laboratory tests. Time to arrest of progression was
determined once the conditions were under control (no new
eruptions, Nikolsky sign turning negative, and exudation
Table 1 Clinical outcome and SCORTEN scores for patients with toxic epidermal necrolysis caused by Dalbergia
cochinchinensis
No./age (years)/sex TBSA (%) Time 1 (days) Time 2 (days)
1/31/M 36 7 9
2/39/M 34 3 10
3/42/M 42 2 13
4/46/M 60 2 16
5/43/M 41 6 19
6/34/F 33 2 16
7/46/M 55 3 7
8/28/M 62 4 7
F, female; M, male; TBSA, total body surface area; Time 1, time from onset of disease to admission; Time 2, time to arrest of
progression; Time 3, time to tapering of corticosteroid; Time 4, total hospitalization time.
International Journal of Dermatology 2015, 54, 1435–1441
Yang et al.
improved). When re-epithelialization had started, with laboratory
tests satisfactorily monitored and recorded on a daily basis, the
dose of corticosteroid was tapered promptly to avoid the risk of
adverse effects. In addition, sequelae were also evaluated once
per month during the outpatient follow-up of one year after
discharge.
Furthermore, to clarify the etiology of occupational TEN,
history of the exposure to Dalbergia cochinchinensis and
possibly containing toxins in the timber were investigated. Patch
tests were performed three months post-discharge using the
powder of the timber provided by the manufacturers and
processed with white petrolatum vehicle, which was then
compared to the control (TRUE Test Diagnostic Patch for
Allergic Contact Dermatitis; MEKOS Laboratories AS, Hilleroed,
Denmark). The test was carried out according to the
International Contact Dermatitis Research Group
recommendations.
Data were gathered as means  SD. The statistical
comparisons of the nonparametric data from the two groups
were performed using the chi-squared test and Mann–Whitney
U-test, as well as Fisher’s exact probabilities whenever
appropriate; parametric data were compared using Student’s
two-tailed t-test. Statistical significance was defined as
P < 0.05. Statistical analyses were conducted using Stata 8.0
software (Stata Corp., College Station, TX, USA).
Result
Eight cases of TEN of the study group are shown in
Table 1. Among 37 patients admitted with drug-induced
TEN from 2003 to 2012, 15 met the inclusion criteria in
the control group (Table 2). The clinical outcomes of
patients with drug-induced TEN were different; seven
cases of death were excluded because their SCORTEN
scores were ≥4. The culprit drugs of the control group
were allopurinol (two cases), carbamazepine (two), amox-
icillin (two), Chinese herbal medicine (two), cephalospo-
Time 3 (days) Time 4 (days) SCORTEN
13 30 1
15 22 1
15 20 2
19 29 2
25 36 2
18 26 1
10 26 2
10 21 1
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Yang et al. Occupational toxic epidermal necrolysis Pharmacology and therapeutics 1437

Table 2 Clinical outcome and SCORTEN scores for patients with toxic epidermal necrolysis induced by drug

No./age (years)/sex Culprit drug TBSA (%) Time 1 (days) Time 2 (days) Time 3 (days) Time 4 (days) SCORTEN

1/F/32 Amoxicillin 36 1 3 10 17 1
2/F/50 Dipyridamole 41 3 4 11 17 2
3/M/42 Amoxicillin 32 3 10 12 19 2
4/F/34 Methazolamide 38 2 8 11 20 1
5/M/20 Levetiracetam 55 2 7 7 16 1
6/M/35 Aminopyrine 53 5 7 9 16 1
7/M/22 Metamizole 37 4 7 14 19 1
8/F/28 Carbamazepine 40 2 8 18 27 1
9/M/32 Carbamazepine 60 1 4 12 17 1
10/M/40 Cephalosporins 34 7 7 15 25 2
11/M/29 Chinese herb 67 4 12 15 22 1
12/M/44 Allopurinol 71 3 6 12 21 2
13/F/25 Chinese herb 50 1 8 9 23 1
14/M/21 Allopurinol 3 1 6 9 20 1
15/F/50 Penicillin 46 0 10 12 17 2

F, female; M, male; TBSA, total body surface area; Time 1, time from onset of disease to admission; Time 2, time to arrest of
progression; Time 3, time to tapering of corticosteroid; Time 4, total hospitalization time.

rins (one), penicillin (one), methazolamide (one), dipyri-
damole (one), aminopyrine (one), metamizole (one), and
levetiracetam (one).
Histopathological evaluation of biopsies taken from
patients’ blisters demonstrated subepidermal blister, typi-
cally confluent full-thickness epidermal necrosis (or apop-
tosis in early stage), and interface and perivascular
lymphocyte infiltration (Fig. 2a,b), which supported the
diagnosis of TEN.
In both the eight cases of occupational TEN and the 15
control cases, there were no deaths. While according to
the SCORTEN system, overall expected deaths were
0.612 and 0.836, respectively, the difference of expected
deaths between the two groups was not significant
(P = 0.4455, >0.05). Similarly, there were no differences
in age, time from onset of disease to admission, and total
body surface area admission time between two groups
(38.6  2.4 vs. 35.3  1.9, P = 0.216; 3.63  0.67 vs.
2.60  0.48, P = 0.225; 45.38  4.19 vs. 46.2  3.25,
P = 0.8802). On the contrary, the times to the arrest of
progression were 12.10  1.60 and 7.10  0.62, and the
difference between the two groups was significant
(P = 0.0023, <0.05). Similarly, there were significant
differences in the time to tapering of corticosteroid
(15.60  1.77 vs. 11.73  0.74, P = 0.026) and the
duration of hospital stay (26.25  1.90 vs. 19.73  0.86,
P = 0.0017). These data are also shown in Table 3.
In the study group, there were six patients who suffered
liver transaminase elevations (more than twice of the nor-
mal value) and recovered after liver treatment. This fre-
quency was higher than that of the control group, but the
difference was not statistically significant (six cases of
eight patients vs. seven of 15; P = 0.38, >0.05). In addi-
tion, in the study group there were two cases of hypergly-
cemia (three cases in the control group) and one case of
pulmonary infection (three cases in the control group).
Four patients in the study group and seven in the control
group presented with a high fever (>38.5 °C). The
frequencies were not significantly different between the
two groups for the three measures (P = 1.00).
Sequelae, including blindness and bronchiolitis obliter-
ans, have been reported in previous studies1 but had not
been found in both groups during one year after discharge.
Of a total of 105 workers exposed to Dalbergia cochin-
chinensis in four furniture factories, eight cases of TEN
developed, and 13 cases developed erythema multiforme-

Table 3 Clinical outcomes comparison between the study group and the control group

Age (years) TBSA (%) Time 1 (days) Time 2 (days) Time 3 (days) Time 4 (days)

Study group 38.4  2.4 45.38  4.19 3.63 0.67 12.10  1.60 15.60  1.77 26.25  1.90
Control group 35.3  1.9 46.2  3.25 2.60 0.48 7.10  0.62 11.73  0.74 19.73  0.86
P value 0.216 0.8802 0.225 0.0023 0.026 0.0017

TBSA, total body surface area; Time 1, time from onset of disease to admission; Time 2, time to arrest of progression; Time 3,
time to tapering of corticosteroid; Time 4, total hospitalization time.

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1438 Pharmacology and therapeutics Occupational toxic epidermal necrolysis Yang et al.

like eruptions, but the eruptions vanished after treatment (a)

with oral antihistamines and corticosteroid cream for
one week. Under the same strength of exposure, 84 work-
ers were not affected. Five to 10 days before the onset, the
workshop began to process this timber. The paint and coat-
ing in the factories had not changed for six months before
processing this timber. In each factory, the occupational
health supervision department conducted an investigation
after the incidents, and the air testing result was normal.
Furthermore, we tested the existence of trichlorethylene,
acrylonitrile, phosphate pesticide, thiourea dioxide, and
chlorobenzene in this timber, which most frequently
resulted in severe occupational skin diseases in China.
However, the results were all negative.
With informed consent, one patient received a patch
test. After 48 hours, the testing area developed erythema (b)
with edema and erosion, along with unbearable itching,
which presented a positive (3+) reaction (Fig. 3a). The
patient requested that the test was stopped before its
completion, so we discontinued the process, and the con-
dition resolved with corticosteroid cream.

Discussion
TEN caused by non-drug factors is generally a rare occur-
rence, and TEN is regarded as a type of severe cutaneous
adverse drug reaction.7,8 The patients admitted to our
department had no medication history, atopic dermatitis,
herpes simplex, or other infectious disease during the
previous months. Their skin was manifested as atypical
erythema multiforme and bullous. The exfoliative area was (c)
more than 30% of the total body surface (Fig. 1a–c), which
was in line with the TEN diagnostic criteria.9 However, the
mucosa was only mildly involved. Skin in the non-contact-
ing area also developed erythema with bullae. The symp-
tom progressively worsened when patients were removed
from the environment, which did not support the diagnosis
of occupational contact dermatitis. In addition, erythema
mutiforme majus (EMM) is often clinically confused with
SJS/TEN, but EMM is generally regarded as the manifesta-
tion of infection, especially herpes simplex virus, rather
than drugs. In histological findings, weak epidermal necro-
sis and significant inflammatory cell infiltration in the der-
mis are typical findings in EMM, and extensive epidermal
necrosis and minimal inflammatory infiltration are charac-
Figure 1 (a) Patient 1: first day of admission; dark black
teristic of SJS/TEN.10 In consequence, both clinical and his-
atypical erythema multiforme-like rash on back, integrated
tological findings supported the diagnosis of TEN rather
into patches, with flaccid bullae and positive Nikolsky
than EMM. To confirm this diagnosis, skin biopsies and sign, epidermal detachment >30% total body surface
patch tests were performed. Histopathological evaluation area. (b) Patient 2: typical epidermal detachment
of biopsies taken from blisters of the patients demonstrated presented scalded appearance. (c) Patient 1: 7 d after
subepidermal blisters, typically confluent full-thickness epi- admission, large desquamation but mucous membrane
dermal necrosis, and interface and perivascular lymphocyte mildly involved

International Journal of Dermatology 2015, 54, 1435–1441 ª 2015 The International Society of Dermatology
Yang et al. Occupational toxic epidermal necrolysis Pharmacology and therapeutics 1439

(a) (a)

(b)
(b)

(c)

Figure 2 (a) Skin specimens from blisters of patient 1 stained

with hematoxylin and eosin showed lots of apoptosis cells in
blister roof epidermis, which are generally seen in early
stage, dermal perivascular lymphocytic infiltration with a few
neutrophils (original magnification 9400). (b) Skin specimens
from blisters of patient 2 stained with hematoxylin and eosin
showed subepidermal blister, typically confluent full-
thickness epidermal necrosis, and interface and perivascular
lymphocytes infiltration. Compared with (a), keratinocyte
damage was more severe with diagnostically sparse
lymphocytes infiltration (original magnification 9400)

infiltration (Fig. 2a,b), which supported the diagnosis of

TEN.
In our study, other possible causes of the occupational
TEN, especially chemical toxins, were presumed, but based
on our available techniques, there was no evidence to
support this hypothesis. One of the patch tests supported
that timber might be the cause of the disease, but that was
not enough. Ultimately, we determined this occupational
TEN was associated with the timber. Because mucous
membrane and pulmonary function were mildly involved,
Figure 3 (a) Patch test, erythema with edema and erosion
after 48 h while the controls were negative. (b) Targeted
lesions continuously appeared on thigh when bullae
disappeared. (c) Targeted lesions continuously appeared on
leg when bullae disappeared
it was unlikely that inhalation of dust was the route of
exposure. We considered skin contact and absorption
through skin might be the most probable route.

ª 2015 The International Society of Dermatology International Journal of Dermatology 2015, 54, 1435–1441
1440 Pharmacology and therapeutics Occupational toxic epidermal necrolysis
Under the same strength of the exposure, sufferers that
developed TEN were in a tiny minority while the major-
ity of them showed no response, which is similar to drug-
induced TEN due to idiosyncrasia. Compared with nevi-
rapine, which was documented as the strongest associa-
tion with SJS/TEN,11 there is no significant difference
between the two frequencies (eight of 105 vs. 21 of 309,
P = 0.775).
There is no well-established treatment for TEN. Sys-
temic corticosteroid therapy has been very controver-
sial.7,8,12,13 TEN has routinely been treated with systemic
corticosteroids in China. It can halt progression of the dis-
ease, but the dose should be tapered rapidly when the dis-
ease has been controlled to avoid adverse effects, such as
delayed re-epithelialization and severe infection. In addi-
tion, the use of IVIG in the treatment of TEN is often rec-
ommended,9,14 although a meta-analysis performed
recently does not support the clinical benefit of IVIG.10,15
We prefer combination therapy of corticosteroid and IVIG
as it had achieved a better therapeutic effect than the
administration of corticosteroid alone. In our study, 23
cases of TEN, including occupational and drug-induced
ones, were both cured by this treatment without sequelae.
In conclusion, compared to drug-induced TEN, occupa-
tional TEN caused by Dalbergia cochinchinensis had a
similar clinical course but was harder to control. We
observed that the skin area at the site without blister con-
tinued to develop new targeted lesions even when bullae
disappeared and led to desquamation (Fig. 3a–c); these
targeted lesions were regarded as typical erythema multi-
forme and seldom observed in drug-induced TEN.10,11
We presumably considered that residual toxins were diffi-
cult to discharge and continued to stimulate the body’s
immune system.
Based on the study, we recommend our dermatologists
pay attention to this special type of TEN, which seems to
be more complicated. Such diseases occurred mostly in
the summer. The hot working environment and lack of
occupational protection may lead to incidences of the
disease. Given the severity of the disease, strengthening
the protection for workers in the furniture industry is
necessary.
We acknowledge that there are constraints in this
study. The exact substances or toxins in this timber have
not been identified, which makes targeted therapy not
possible. Patch tests may be useful for identifying agents
inducing TEN16 but need to be monitored carefully given
the severe reaction history;17 with informed consent, only
one patient received patch testing, which was discontin-
ued after 48 hours. The limited number of patients in
each group may result in a statistically insignificant differ-
ence. More in-depth research is needed to further under-
stand the cause and the cure of this disease.
International Journal of Dermatology 2015, 54, 1435–1441
Yang et al.
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