Journal of Critical Care 42 (2017) 65–68

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Successful treatment of toxic epidermal necrolysis using plasmapheresis:

A prospective observational study
Feng Han, MD a,1, Jingjing Zhang, MD b,1, Qi Guo, MD c, Yanjing Feng, MD b, Ya Gao, MD b, Litao Guo, MD d,
Yanli Hou, MD a, Jingang An, MD e, Xiaopeng Wang, MD, PhD e, Bin Yan, MD b, Yan Zheng, MD, PhD e,
Jingchun Song, MD, PhD f, Manxiang Li, MD, PhD g,⁎, Gang Wang, MD, PhD b,⁎
a
Intensive Care Unit, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
b
Department of Emergency Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
c
Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
d
Intensive Care Unit, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
e
Department of Dermatology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
f
Intensive Care Unit, The 94th PLA Hospital, Nanchang, China
g
Department of Respiratory Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China

a r t i c l e i n f o a b s t r a c t

Keywords: Toxic epidermal necrolysis (TEN) is a rare, severe, life-threatening skin disease and it requires urgent critical care,
Toxic epidermal necrolysis including admission to the intensive care unit (ICU). It is characterized by fatal sequelae and high mortality. Cur-
Stevens–Johnson syndrome rently, insufficient evidence exists to support the use of any systemic adjuvant therapy, such as cyclophospha-
Plasmapheresis mide, intravenous immunoglobulin (IVIg), or corticosteroids. However, plasmapheresis has been increasingly
Corticosteroids
valued by clinicians due to its significant efficacy and little adverse side effects. To assess the efficacy of such treat-
Immunoglobulin
ment, 28 patients who were diagnosed with TEN or SJS/TEN overlap were continuously recruited in the ICU from
Intensive care unit
February 2009 to August 2016. These patients including both children and adults were randomly divided into
two groups based on whether or not plasmapheresis therapy was performed after admission, which resulted
in a plasmapheresis group (n = 13) and a non-plasmapheresis group (n = 15). Severity of the disease and the
efficacy of treatments were evaluated by the severity-of-illness score for TEN. The results indicated that plasma-
pheresis may be superior to conventional therapies, such as IVIg or corticosteroids. Furthermore, plasmapheresis
combined with other treatments might not be advantageous compared to the effect of plasmapheresis alone.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction
Toxic epidermal necrolysis (TEN) is a rare, severe, life-threatening
skin disease characterized by extensive exfoliation of the epidermis
and skin mucous membrane that is accompanied by systemic distur-
bances [1]. It is mainly induced by adverse drug reactions arising mostly
from antibiotics, anti-retroviral therapies, allopurinol, anti-convulsants,
or nonsteroidal anti-inflammatory drugs (NSAIDs) [2,3]. The vital char-
acteristics of TEN include low morbidity, fatal sequelae, and high mor-
tality in the intensive care unit (ICU). In a narrow sense, TEN is the
most severe skin disease with maximum epidermal detachment of
≥ 30% body surface area (BSA) after admission. As a milder form of
TEN, patients with SJS/TEN overlap exhibit less severe skin damage,
which affects approximately 10%–30% of their body surface compared
⁎ Corresponding authors.
E-mail addresses: manxiangli@xjtu.edu.cn (M. Li), gang_wang@mail.xjtu.edu.cn
(G. Wang).
1
Drs. Han and Zhang contributed equally to this work.
to N 30% in TEN [4]. Although many studies have stressed the impor-
tance of the early diagnosis and rapid withdrawal of causative drugs
and active adjuvant therapy, the best administrative strategy for con-
trolling pathological progress and reducing the mortality of TEN re-
mains controversial [1,5].
A literature review returned no convincing evidence to support the
use of any systemic adjuvant therapy. A previous study has demonstrat-
ed that intravenous immunoglobulin (IVIg) could inhibit Fas-FasL medi-
ated keratinocyte apoptosis in vitro [6]. Unfortunately, this was not
consistent with the finding that IVIg failed to improve the survival rate
of patients with TEN [1]. Moreover, because of their rapid anti-inflam-
matory effects, corticosteroids have become another popular treatment
option for TEN [3,7]. However, systemic corticosteroids increase the risk
of sepsis, which accelerates multiple organ damage and leads to higher
mortality [8].
A range of other therapies, such as plasmapheresis, cyclophospha-
mide, cyclosporine, pentoxifylline, N-acetylcysteine, ulinastatin, and
infliximab, have also been used in the treatment of TEN [9]. However,
there is no clear and compelling evidence that supports the use of any

http://dx.doi.org/10.1016/j.jcrc.2017.07.002
0883-9441/© 2017 Elsevier Inc. All rights reserved.
66 F. Han et al. / Journal of Critical Care 42 (2017) 65–68
of the above systemic adjuvant therapies. Although plasmapheresis is
increasingly used by doctors in the ICU and researchers due to its signif-
icant advantages in reducing the mortality of TEN and shortening hospi-
tal stays, no results from prospective observational studies or
randomized controlled trials have been provided [10,11]. In this study,
we prospectively reviewed a group of 28 patients with TEN or SJS/TEN
overlap admitted to the ICU. The basic clinical information of patients,
the therapeutic effect, as evaluated using scores, and total medical ex-
penditures were compared among different groups to confirm the effec-
tiveness of plasmapheresis therapy.
2. Materials and methods
2.1. Design and study population
Twenty-eight patients with TEN or SJS/TEN overlap who were ad-
mitted to the ICU of the second affiliated hospital of Xi'an Jiaotong Uni-
versity from February 2009 to August 2016 were prospectively
recruited. According to the 2016 United Kingdom guidelines for the
management of SJS/TEN in adults, TEN is defined as epidermal detach-
ment of N 30% of the BSA, and SJS/TEN overlap is defined as detachment
of 10%–30% of the total BSA [12]. Patients with a maximum epidermal
detachment of 10–30% of the BSA were also incorporated into the TEN
group in this study [1].
2.2. Group and treatments
All patients were randomly divided into either the plasmapheresis
group (n = 13) or the non-plasmapheresis group (n = 15) on the
basis of whether plasma exchange was performed after admission. Sub-
sequently, the plasmapheresis group was further divided into two sub-
groups: the pure plasmapheresis group, whose members were treated
with plasmapheresis alone (n = 6), and the co-plasmapheresis group,
whose members were treated with plasmapheresis in combination
with glucocorticoids and/or IVIg (n = 7). In addition, Plasmapheresis
therapy was performed only once in all occasions with 1000 ml of Ring-
er-Locke and 2000–3000 ml of plasma at a rate of 1000 ml an hour. Glu-
cocorticoids and IVIg were given according to the latest guidelines [12].
2.3. Effect evaluation
The primary efficacy end-point was the response rate as evaluated
by the change in the severity-of-illness score between admission and
discharge as well as the recovery velocity index (RVI). The severity-of-
illness score was established for this study to evaluate the efficacy
after the therapy. It is a rating scale that scores ophthalmic lesions, lip/
oral lesions, cutaneous lesions and general condition, with a total
score ranging 0–39 (see Supplementary Table 1) [13]. Recovery velocity
index (RVI) is calculated using the differences in TEN score between ad-
mission and discharge divided by the time of hospital stay. This reflects
the speed of recovery from illness. The secondary efficacy end-point in-
cluded changes over time in the severity-of-illness score on the 4th, 7th,
10th, and 20th days of the treatments. The above scores were evaluated
as short-term treatment outcomes. Additionally, total expenditures in
the hospital were also calculated.
2.4. Statistical analysis
Standard descriptive statistics were used to describe the study sam-
ple. We first conducted a normality test and assessed the homogeneity
of variance for all variables. An independent-sample t-test was used to
analyze continuous data that were normally distributed. Two-indepen-
dent-sample test in the nonparametric tests (namely the Mann-Whit-
ney U test) was used for quantitative data that was non-normally
distributed and the Chi-square test was used for binary variables be-
tween different groups. The statistical results are presented as
percentages for discrete variables and as means ± standard deviation
or median (P25, P75) for continuous variables. All data were analyzed
using SPSS V.22.0.
3. Results
There were no statistical differences with respect to the children/
adult ratio, male/female ratio, and stripping area after admission be-
tween the plasmapheresis group and non-plasmapheresis group
(Table 1). We found no statistical difference in the severity-of-illness
score on the 1st and 4th day after admission between the two groups.
However, the scores of the plasmapheresis group were lower than
those of the non-plasmapheresis group on the 7th, 10th, and 20th day
of admission [12.00 (10.00, 18.50) vs 19.00 (13.00, 33.00), P = 0.025;
6.50 (4.00, 7.75) vs 26.00 (10.25, 32.75), P b 0.001; 2.63 ± 2.82 vs
20.30 ± 12.53, P = 0.001; respectively] (Fig. 1). Furthermore, score
change between admission and discharge also demonstrated a signifi-
cant difference between the two groups (28.23 ± 4.91 vs 12.50 ±
13.19, P b 0.001).
Furthermore, we created a recovery velocity index (RVI) of TEN to
evaluate the recovery rate of TEN by treatment. Notably, the rate of re-
covery in the plasmapheresis group was higher than in the non-plasma-
pheresis group (2.49 ± 1.02 vs 0.88 ± 0.99, P b 0.001). However, in
subgroup analysis, in addition to the stripping area after admission
[23.00(17.25,36.75) vs 40.00(35.00,50.00), P = 0.035], there were no
statistical differences with respect to age, gender, the system score,
RVI and total expenditure between the pure plasmapheresis group
and co-plasmapheresis group (P N 0.05) (see Supplementary Table 2).
The Supplementary Table 3 shows the original data for all patients.
4. Discussion
TEN is a severe cutaneous disease characterized by epidermal de-
tachment and mucus erosion with a mortality rate of over 30% and an
annual incidence of approximately 0.4–1.2 cases per million individuals
[14]. This high mortality results not only from the extensively denuded
skin area but also from the systemic complications, such as sepsis, dis-
seminated intra-vascular coagulation (DIC), and multiple organ failure.
The disorder is mainly induced by adverse drug reactions, which include
antibiotics, anticonvulsants, anti-retroviral drugs, NSAIDS, and allopuri-
nol [15]. Therefore, it is obligatory for these patients to discontinue the
relevant agents and receive supportive therapies in the intensive care
unit [3].
There is an abundance of clinical anecdotes that indicate a therapeu-
tic benefit of corticosteroids, IVIg and plasmapheresis; however, these
therapies are not supported by prospectively observational or random-
ized controlled experiments. In the current study, we observed that
plasmapheresis therapy might be superior to IVIg, corticosteroids, or
even a combination of the two. Furthermore, the single plasmapheresis
strategy was found to be just as effective as combination therapy that
included plasmapheresis and IVIg and/or glucocorticoids regarding the
extent and speed of the reduction in the TEN score and total
expenditure.
Previously, it has been reported that extensive keratinocyte apopto-
sis plays a critical role in the pathogenesis of TEN, where the soluble Fas
ligand, perforin and granzyme have been implicated in triggering
keratinocyte apoptosis or necrosis. However, a recent study found that
granulysin is believed to be a key mediator of this process [12]. Although
there is evidence for the use of IVIg in the acute management of SJS/TEN
at the recommended dose of 2–3 g/kg, other findings have indicated
that this type of treatment was less favorable as there was no survival
benefit when compared with supportive care alone [16]. Corticosteroids
administration was once regarded as a promising and effective treat-
ment that could quickly relieve the clinical symptoms of TEN [17]. How-
ever, other reports have proposed that systemic corticosteroids might
increase the risk of sepsis [12,18].
 F. Han et al. / Journal of Critical Care 42 (2017) 65–68 67

Table 1
Comparison between plasmapheresis and non-plasmapheresis.

Variable Plasmapheresis Non-plasmapheresis P value

Patients, n 13 15
Children/adult, n 4/9 3/12 0.670
Age, year 19(7,48.5) 31(17,70) 0.217
Male/female, n 7/6 8/7 0.978
Onset to admission time, d 10.36 ± 7.10 5.77 ± 3.70 0.054
Stripping area, % 35.00(23.00,46.50) 30.00(12.00,66.00) 0.555
Admission score 31.31 ± 5.04 28.67 ± 8.56 0.326
Discharge score 3.00(1.50,4.50) 8.00(0.00,30.00) 0.052
Score difference between admission and discharge 28.23 ± 4.91 12.50 ± 13.19 b0.001
D1 score 31.46 ± 4.96 28.60 ± 8.72 0.306
D4 score 24.08 ± 5.29 26.80 ± 8.97 0.347
D7 score 12.00(10.00,18.50) 19.00(13.00,33.00) 0.025
D10 score 6.50(4.00,7.75) 26.00(10.25,32.75) b0.001
D20 score 2.63 ± 2.82 20.30 ± 12.54 0.001
RVI 2.49 ± 1.02 0.89 ± 0.99 b0.001
Total expenditure 56,039.71(49,812.79,71,858.89) 37,506.52(17,627.18,83,409.22) 0.424

D, day.
RVI = (TEN score at admission minus score at discharge)/total time of hospital stay.
The results of the independent-sample t-test are presented as the mean ± SD, results of the Wilcoxon test are presented as the median (P25, P75), and results of the Chi-square test are
presented as a number. P b 0.05 was considered statistically significant.

In the recent years, plasmapheresis has been reported to improve
the clinical symptoms in severe and refractory TEN patients [19-22]. In-
deed, Egan et al. affirmed the effectiveness of plasma exchange by com-
paring the mortality between the plasmapheresis group and the
conventional supportive therapy in 1999 [23]. However, plasmaphere-
sis has not attracted sufficient attention due to the potential risks of
transfusion-associated therapies and its cost [23]. Most previous studies
were published as case reports or case series due to a fairly low inci-
dence rate and thus could not be generalized to other cases [24,25].
Our study was performed with a prospective design and a small
sample size in northwestern China. As we only compared the advan-
tages of plasmapheresis, corticosteroids and IVIg therapies, differences
and similarities between plasmapheresis and other treatments, such
as cyclophosphamide, cyclosporine, N-acetylcysteine, and infliximab,
are unknown. Moreover, randomized controlled trials are challenging
to perform as the administration of plasmapheresis, corticosteroids
and IVIg therapies require consent from patients or their custodians.
Therefore, long-term prospective studies with a larger number of pa-
tients are still needed to validate our results.
5. Conclusions
Plasmapheresis as a first line therapeutic strategy might present sig-
nificant advantages in comparison to glucocorticoids and/or IVIg in re-
ducing the mortality of TEN patients as well as in shortening the
duration of stays in the intensive care unit. Furthermore, plasmaphere-
sis combined with the IVIg or/and glucocorticoids might not be advan-
tageous compared to the effect of plasmapheresis alone. Further
research is needed to confirm these results.

Fig. 1. A plot of score change demonstrates differences with respect to therapy. Within the line chart, rows represent admission time while columns represent the score difference value
between the 4th, 7th, 10th, and 20th days of admission compared with the first day. We observed that the score change in the group treated with plasmapheresis therapy is notably higher
than the score change in patients treated with non-plasmapheresis therapy.
68 F. Han et al. / Journal of Critical Care 42 (2017) 65–68
Funding
This work was supported by the Scientific Fund for the Young Talent
of Shaanxi Province (2015KJXX-06).
Conflicts of interest
None.
Acknowledgments
We are grateful to Dr. Xiaofeng Zhang from the Department of Statis-
tics at the Xi'an Jiaotong University School of Medicine for her advice on
statistical methods. We thank the patients for their cooperation while
participating in our research.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.jcrc.2017.07.002.
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