You are on page 1of 4

Journal of Critical Care 42 (2017) 65–68

Contents lists available at ScienceDirect

Journal of Critical Care

journal homepage:

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,⁎
Intensive Care Unit, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Department of Emergency Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Intensive Care Unit, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Department of Dermatology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Intensive Care Unit, The 94th PLA Hospital, Nanchang, China
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
valued by clinicians due to its significant efficacy and little adverse side effects. To assess the efficacy of such treat-
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 to N 30% in TEN [4]. Although many studies have stressed the impor-
tance of the early diagnosis and rapid withdrawal of causative drugs
Toxic epidermal necrolysis (TEN) is a rare, severe, life-threatening and active adjuvant therapy, the best administrative strategy for con-
skin disease characterized by extensive exfoliation of the epidermis trolling pathological progress and reducing the mortality of TEN re-
and skin mucous membrane that is accompanied by systemic distur- mains controversial [1,5].
bances [1]. It is mainly induced by adverse drug reactions arising mostly A literature review returned no convincing evidence to support the
from antibiotics, anti-retroviral therapies, allopurinol, anti-convulsants, use of any systemic adjuvant therapy. A previous study has demonstrat-
or nonsteroidal anti-inflammatory drugs (NSAIDs) [2,3]. The vital char- ed that intravenous immunoglobulin (IVIg) could inhibit Fas-FasL medi-
acteristics of TEN include low morbidity, fatal sequelae, and high mor- ated keratinocyte apoptosis in vitro [6]. Unfortunately, this was not
tality in the intensive care unit (ICU). In a narrow sense, TEN is the consistent with the finding that IVIg failed to improve the survival rate
most severe skin disease with maximum epidermal detachment of of patients with TEN [1]. Moreover, because of their rapid anti-inflam-
≥ 30% body surface area (BSA) after admission. As a milder form of matory effects, corticosteroids have become another popular treatment
TEN, patients with SJS/TEN overlap exhibit less severe skin damage, option for TEN [3,7]. However, systemic corticosteroids increase the risk
which affects approximately 10%–30% of their body surface compared of sepsis, which accelerates multiple organ damage and leads to higher
mortality [8].
A range of other therapies, such as plasmapheresis, cyclophospha-
⁎ Corresponding authors.
E-mail addresses: (M. Li),
mide, cyclosporine, pentoxifylline, N-acetylcysteine, ulinastatin, and
(G. Wang). infliximab, have also been used in the treatment of TEN [9]. However,
Drs. Han and Zhang contributed equally to this work. there is no clear and compelling evidence that supports the use of any
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 percentages for discrete variables and as means ± standard deviation
increasingly used by doctors in the ICU and researchers due to its signif- or median (P25, P75) for continuous variables. All data were analyzed
icant advantages in reducing the mortality of TEN and shortening hospi- using SPSS V.22.0.
tal stays, no results from prospective observational studies or
randomized controlled trials have been provided [10,11]. In this study, 3. Results
we prospectively reviewed a group of 28 patients with TEN or SJS/TEN
overlap admitted to the ICU. The basic clinical information of patients, There were no statistical differences with respect to the children/
the therapeutic effect, as evaluated using scores, and total medical ex- adult ratio, male/female ratio, and stripping area after admission be-
penditures were compared among different groups to confirm the effec- tween the plasmapheresis group and non-plasmapheresis group
tiveness of plasmapheresis therapy. (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.
2. Materials and methods However, the scores of the plasmapheresis group were lower than
those of the non-plasmapheresis group on the 7th, 10th, and 20th day
2.1. Design and study population 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
Twenty-eight patients with TEN or SJS/TEN overlap who were ad- 20.30 ± 12.53, P = 0.001; respectively] (Fig. 1). Furthermore, score
mitted to the ICU of the second affiliated hospital of Xi'an Jiaotong Uni- change between admission and discharge also demonstrated a signifi-
versity from February 2009 to August 2016 were prospectively cant difference between the two groups (28.23 ± 4.91 vs 12.50 ±
recruited. According to the 2016 United Kingdom guidelines for the 13.19, P b 0.001).
management of SJS/TEN in adults, TEN is defined as epidermal detach- Furthermore, we created a recovery velocity index (RVI) of TEN to
ment of N 30% of the BSA, and SJS/TEN overlap is defined as detachment evaluate the recovery rate of TEN by treatment. Notably, the rate of re-
of 10%–30% of the total BSA [12]. Patients with a maximum epidermal covery in the plasmapheresis group was higher than in the non-plasma-
detachment of 10–30% of the BSA were also incorporated into the TEN pheresis group (2.49 ± 1.02 vs 0.88 ± 0.99, P b 0.001). However, in
group in this study [1]. 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
2.2. Group and treatments statistical differences with respect to age, gender, the system score,
RVI and total expenditure between the pure plasmapheresis group
All patients were randomly divided into either the plasmapheresis and co-plasmapheresis group (P N 0.05) (see Supplementary Table 2).
group (n = 13) or the non-plasmapheresis group (n = 15) on the The Supplementary Table 3 shows the original data for all patients.
basis of whether plasma exchange was performed after admission. Sub-
sequently, the plasmapheresis group was further divided into two sub- 4. Discussion
groups: the pure plasmapheresis group, whose members were treated
with plasmapheresis alone (n = 6), and the co-plasmapheresis group, TEN is a severe cutaneous disease characterized by epidermal de-
whose members were treated with plasmapheresis in combination tachment and mucus erosion with a mortality rate of over 30% and an
with glucocorticoids and/or IVIg (n = 7). In addition, Plasmapheresis annual incidence of approximately 0.4–1.2 cases per million individuals
therapy was performed only once in all occasions with 1000 ml of Ring- [14]. This high mortality results not only from the extensively denuded
er-Locke and 2000–3000 ml of plasma at a rate of 1000 ml an hour. Glu- skin area but also from the systemic complications, such as sepsis, dis-
cocorticoids and IVIg were given according to the latest guidelines [12]. seminated intra-vascular coagulation (DIC), and multiple organ failure.
The disorder is mainly induced by adverse drug reactions, which include
2.3. Effect evaluation antibiotics, anticonvulsants, anti-retroviral drugs, NSAIDS, and allopuri-
nol [15]. Therefore, it is obligatory for these patients to discontinue the
The primary efficacy end-point was the response rate as evaluated relevant agents and receive supportive therapies in the intensive care
by the change in the severity-of-illness score between admission and unit [3].
discharge as well as the recovery velocity index (RVI). The severity-of- There is an abundance of clinical anecdotes that indicate a therapeu-
illness score was established for this study to evaluate the efficacy tic benefit of corticosteroids, IVIg and plasmapheresis; however, these
after the therapy. It is a rating scale that scores ophthalmic lesions, lip/ therapies are not supported by prospectively observational or random-
oral lesions, cutaneous lesions and general condition, with a total ized controlled experiments. In the current study, we observed that
score ranging 0–39 (see Supplementary Table 1) [13]. Recovery velocity plasmapheresis therapy might be superior to IVIg, corticosteroids, or
index (RVI) is calculated using the differences in TEN score between ad- even a combination of the two. Furthermore, the single plasmapheresis
mission and discharge divided by the time of hospital stay. This reflects strategy was found to be just as effective as combination therapy that
the speed of recovery from illness. The secondary efficacy end-point in- included plasmapheresis and IVIg and/or glucocorticoids regarding the
cluded changes over time in the severity-of-illness score on the 4th, 7th, extent and speed of the reduction in the TEN score and total
10th, and 20th days of the treatments. The above scores were evaluated expenditure.
as short-term treatment outcomes. Additionally, total expenditures in Previously, it has been reported that extensive keratinocyte apopto-
the hospital were also calculated. sis plays a critical role in the pathogenesis of TEN, where the soluble Fas
ligand, perforin and granzyme have been implicated in triggering
2.4. Statistical analysis keratinocyte apoptosis or necrosis. However, a recent study found that
granulysin is believed to be a key mediator of this process [12]. Although
Standard descriptive statistics were used to describe the study sam- there is evidence for the use of IVIg in the acute management of SJS/TEN
ple. We first conducted a normality test and assessed the homogeneity at the recommended dose of 2–3 g/kg, other findings have indicated
of variance for all variables. An independent-sample t-test was used to that this type of treatment was less favorable as there was no survival
analyze continuous data that were normally distributed. Two-indepen- benefit when compared with supportive care alone [16]. Corticosteroids
dent-sample test in the nonparametric tests (namely the Mann-Whit- administration was once regarded as a promising and effective treat-
ney U test) was used for quantitative data that was non-normally ment that could quickly relieve the clinical symptoms of TEN [17]. How-
distributed and the Chi-square test was used for binary variables be- ever, other reports have proposed that systemic corticosteroids might
tween different groups. The statistical results are presented as 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 to perform as the administration of plasmapheresis, corticosteroids
the clinical symptoms in severe and refractory TEN patients [19-22]. In- and IVIg therapies require consent from patients or their custodians.
deed, Egan et al. affirmed the effectiveness of plasma exchange by com- Therefore, long-term prospective studies with a larger number of pa-
paring the mortality between the plasmapheresis group and the tients are still needed to validate our results.
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 5. Conclusions
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]. Plasmapheresis as a first line therapeutic strategy might present sig-
Our study was performed with a prospective design and a small nificant advantages in comparison to glucocorticoids and/or IVIg in re-
sample size in northwestern China. As we only compared the advan- ducing the mortality of TEN patients as well as in shortening the
tages of plasmapheresis, corticosteroids and IVIg therapies, differences duration of stays in the intensive care unit. Furthermore, plasmaphere-
and similarities between plasmapheresis and other treatments, such sis combined with the IVIg or/and glucocorticoids might not be advan-
as cyclophosphamide, cyclosporine, N-acetylcysteine, and infliximab, tageous compared to the effect of plasmapheresis alone. Further
are unknown. Moreover, randomized controlled trials are challenging 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 [9] Fernando SL. The management of toxic epidermal necrolysis. Australas J Dermatol
[10] Bamichas G, Natse T, Christidou F, Stangou M, Karagianni A, Koukourikos S, et al.
This work was supported by the Scientific Fund for the Young Talent Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher 2002;
of Shaanxi Province (2015KJXX-06). 6(3):225–8.
[11] Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-
induced toxic epidermal necrolysis. Arch Dermatol 1985;121(12):1548–9.
Conflicts of interest [12] Creamer D, Walsh SA, Dziewulski P, Exton LS, Lee HY, Dart JK, et al. U.K. guidelines
for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in
adults 2016. Br J Dermatol 2016;174(6):1194–227.
[13] Aihara M, Kano Y, Fujita H, Kambara T, Matsukura S, Katayama I, et al. Efficacy of ad-
ditional i.v. immunoglobulin to steroid therapy in Stevens-Johnson syndrome and
Acknowledgments toxic epidermal necrolysis. J Dermatol 2015;42(8):768–77.
[14] Hoetzenecker W, Mehra T, Saulite I, Glatz M, Schmid-Grendelmeier P, Guenova E,
et al. Toxic epidermal necrolysis. F1000Research, 5. ; 2016.
We are grateful to Dr. Xiaofeng Zhang from the Department of Statis- [15] Calvano RA, Scacchi MF, Sojo MM, Diaz SM, Volonteri VI, Giachetti AC. Toxic epider-
tics at the Xi'an Jiaotong University School of Medicine for her advice on mal necrolysis associated with acute infection by Mycoplasma pneumoniae. Arch Ar-
statistical methods. We thank the patients for their cooperation while gent Pediatr 2013;111(1):e24–7.
[16] Lee HY, Lim YL, Thirumoorthy T, Pang SM. The role of intravenous immunoglobulin
participating in our research. in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a
specialized centre. Br J Dermatol 2013;169(6):1304–9.
Appendix A. Supplementary data [17] Choonhakarn C, Limpawattana P, Chaowattanapanit S. Clinical profiles and treat-
ment outcomes of systemic corticosteroids for toxic epidermal necrolysis: a retro-
spective study. J Dermatol 2016;43(2):156–61.
Supplementary data to this article can be found online at http://dx. [18] Yamane Y, Aihara M, Tatewaki S, Matsukura S, Kanbara T, Yamakawa Y, et al. Anal- ysis of treatments and deceased cases of severe adverse drug reactions—analysis of
46 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arerugi
References [19] Giudice G, Maggio G, Bufano L, Memeo G, Vestita M. Management of toxic epidermal
necrolysis with plasmapheresis and cyclosporine A: our 10 years' experience. Plast
[1] Yamane Y, Matsukura S, Watanabe Y, Yamaguchi Y, Nakamura K, Kambara T, et al. Reconstr Surg Glob Open 2017;5(2):e1221.
Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis [20] Szczeklik W, Nowak I, Seczynska B, Sega A, Krolikowski W, Musial J. Beneficial ther-
in 87 Japanese patients—treatment and outcome. Allergol Int 2016;65(1):74–81. apeutic effect of plasmapheresis after unsuccessful treatment with corticosteroids in
[2] Kumar P, Chauhan A, Charaniya R, Ghosh A, Tandon V. Metolazone associated Ste- two patients with severe toxic epidermal necrolysis. Ther Apher Dial 2010;14(3):
vens Johnson syndrome-toxic epidermal necrolysis overlap. J Clin Diagn Res 2016; 354–7.
10(3):Fd01-02. [21] Pinna A, Nuvoli E, Blasetti F, Posadinu MA, Boscia F. Plasmapheresis, intravenous im-
[3] Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal necrolysis (Lyell's disease). munoglobulins, and autologous serum eyedrops in the acute eye complications of
Burns 2010;36(2):152–63. toxic epidermal necrolysis. Eur J Ophthalmol 2017;21:0.
[4] Struck MF, Hilbert P, Mockenhaupt M, Reichelt B, Steen M. Severe cutaneous adverse [22] Hinc-Kasprzyk J, Polak-Krzemińska A, G M, O-Z I. The use of plasmapheresis in a 4-
reactions: emergency approach to non-burn epidermolytic syndromes. Intensive year-old boy with toxic epidermal necrosis. Anaesthesiol Intensive Ther 2015;47(3):
Care Med 2010;36(1):22–32. 210–3.
[5] Ghislain PD, Roujeau JC. Treatment of severe drug reactions: Stevens-Johnson syn- [23] Egan CA, Grant WJ, Morris SE, Saffle JR, Zone JJ. Plasmapheresis as an adjunct treat-
drome, toxic epidermal necrolysis and hypersensitivity syndrome. Dermatol Online ment in toxic epidermal necrolysis. J Am Acad Dermatol 1999;40(3):458–61.
J 2002;8(1):5. [24] Narita YM, Hirahara K, Mizukawa Y, Kano Y, Shiohara T. Efficacy of plasmapheresis
[6] Andresen M, Boghero Y, Molgo M, Dougnao A, Diaz O. Toxic epidermal necrolysis. for the treatment of severe toxic epidermal necrolysis: is cytokine expression anal-
Therapy in ICU with intravenous immunoglobulins in a case. Rev Med Chil 2000; ysis useful in predicting its therapeutic efficacy? J Dermatol 2011;38(3):236–45.
128(12):1343–8. [25] Simsek I, Cinar M, Erdem H, Pay S, Meric C, Dinc A. Efficacy of plasmapheresis in the
[7] Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens-Johnson syn- treatment of refractory toxic epidermal necrolysis-like acute cutaneous lupus ery-
drome/toxic epidermal necrolysis. Acta Derm Venereol 2007;87(2):144–8. thematosus. Lupus 2008;17(6):605–6.
[8] Dhar S. Systemic corticosteroids in toxic epidermal necrolysis. Indian J Dermatol
Venereol Leprol 1996;62(4):270–1.