Toxic epidermal necrolysis
Part II. Prognosis, sequelae, diagnosis, differential diagnosis,
prevention, and treatment
Robert A. Schwartz, MD, MPH, DSc (Hon), FRCP (Edin), Patrick H. McDonough, MD, and Brian W. Lee, MD, MS
Newark, New Jersey
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187.e1
187.e2 Schwartz, McDonough, and Lee J AM ACAD DERMATOL
AUGUST 2013

Toxic epidermal necrolysis (TEN) is a life-threatening, typically drug-induced, mucocutaneous disease. TEN
has a high mortality rate, making early diagnosis and treatment of paramount importance. New but
experimental diagnostic tools that measure serum granulysin and high-mobility group protein B1 (HMGB1)
offer the potential to differentiate early TEN from other, less serious drug reactions, but these tests have not
been validated and are not readily available. The mainstay of treatment for TEN involves discontinuation of the
offending drug, specialized care in an intensive care unit or burn center, and supportive therapy.
Pharmacogenetic studies have clearly established a link between human leukocyte antigen allotype and
TEN. Human leukocyte antigen testing should be performed on patients of East Asian descent before the
initiation of carbamezapine and on all patients before the initiation of abacavir. The effectiveness of systemic
steroids, intravenous immunoglobulins, plasmapheresis, cyclosporine, biologics, and other agents is
uncertain. ( J Am Acad Dermatol 2013;69:187.e1-16.)

Key words: biologics; cyclosporine; drug eruption; erythema multiforme; granulysin; intravenous immuno-
globulin; plasmapheresis; penicillin; StevenseJohnson syndrome; systemic steroids; toxic epidermal necrolysis.

PROGNOSIS (Table I). It allots 1 point for

d The mortality rate in
toxic epidermal necroly-
CAPSULE SUMMARY each of 7 variables: (1) age
[40 years; (2) heart rate
Toxic epidermal necrolysis is an acute,
[120 beats per minute; (3)
d

sis is approximately 25%

to 30%
Toxic epidermal necroly-
sis (TEN) is an acute, usually
drug-induced, mucocutane-
ous eruption that is
associated with severe mor-
bidity and mortality (Fig 1).
The mortality rate of
StevenseJohnson syndrome
(SJS) varies between 1% and
5%, while TEN ranges from
25% to 30%.1 A comprehen-
sive survival analysis of
SJS/TEN patients based on
data collected in the
European Registry of
Severe Cutaneous Adverse
Reactions (RegiSCAR) found
that the mortality rate was
23% at 6 weeks and 34% at
1 year.2 Sepsis leading to
multiorgan failure is the
most common cause of
death, with additional mor-
bidity from gastrointestinal
bleeding, pulmonary embo-
lism, myocardial infarction,
and pulmonary edema.3 A
compilation called the
Severity of Illness Score for
Toxic Epidermal Necrolysis
(SCORTEN) was developed
to assess the severity of ill-
ness and predict mortality in
patients with acute TEN
systemic, blistering condition that results
in full thickness denudation of the skin,
involving the cutaneous and mucosal
surfaces, which has a mortality rate of
approximately 25% to 30%.
d The differential diagnosis for toxic
epidermal necrolysis includes
staphylococcal scalded skin syndrome,
drug-induced linear immunoglobulin A
dermatosis, acute graft versus host
disease, acute generalized
exanthematous pustulosis,
erythroderma, drug reaction with
eosinophilia and systemic symptoms,
and most commonly, a generalized
morbilliform eruption.
d In the future, serum granulysin and high-
mobility group protein B1 testing may
prove effective in diagnosing selected
patients with early toxic epidermal
necrolysis, which clinically and histologically
resembles a common morbilliform drug
eruption.
d
Suspect medications should immediately
be discontinued and patients should be
transferred to the intensive care unit or
burn center for supportive therapy,
including dressing of denuded skin.
d
The effectiveness of adjuvant therapies
including systemic steroids, intravenous
immunoglobulins, plasmapheresis,
cyclosporine, and biologics has not been
convincingly shown; thus, use may or
may not be considered.
comorbid malignancy; (4)
epidermal detachment
[10% of body surface area
(BSA) on day 1; (5)
blood urea nitrogen [28
mg/dL; (6) glucose [252
mg/dL; and (7) bicarbonate
\20mEq/L. Mortality in-
creases from 3.2% for a pa-
tient with 0 to 1 point to
35.3% for a patient with 3
points and up to 90.0% for
those with $ 5 points.4 The
accuracy of the SCORTEN
has been validated since the
original study.5,6 In addition,
SCORTEN must be per-
formed on day 1 and day 3
postadmission to optimize
the predictive value of this
tool.7 Finally, the SCORTEN
may underestimate mortality
in patients with respiratory
involvement.8
Patients surviving the acute
phase of TEN retain a signifi-
cant risk of morbidity, with
one study reporting a 65% 5-
year survival rate. This analy-
sis found that an increased
risk of death after discharge
was associated with older age,
a SCORTEN score between 3
and 6, [1 comorbidity, a de-
lay of [5 days between the
onset of TEN and admission to
J AM ACAD DERMATOL Schwartz, McDonough, and Lee 187.e3
VOLUME 69, NUMBER 2

following formula that predicts the odds of mortality

Abbreviations used:
for patients with TEN:
ALDEN: algorithm for drug causality for 11.5 1 (0.1 3 patient’s age 1 0.03 3 total BSA
epidermal necrolysis
BSA: body surface area involvement 1 5.75 if sepsis is present).
EM: erythema multiforme
EMm: erythema multiforme minor
EMM: erythema multiforme major SEQUELAE
FasL: Fas ligand
GCSF: granulocyte colony-stimulating factor d Patients are at risk for a host of sequelae,
HLA: human leukocyte antigen including cutaneous scarring, ocular lesions,
HMGB1: high-mobility group protein B1 dyspigmentation, dental complications,
IVIG: intravenous immunoglobulin
LTT: lymphocyte transformation testing genitourinary problems, and pulmonary
NAC: N-acetylcysteine disease
SCORTEN: severity of illness score for toxic
epidermal necrolysis Patients surviving the acute phase of TEN are
SJS: StevenseJohnson syndrome
SSSS: staphylococcal scalded skin syndrome also at risk for a host of sequelae (Table II),
TEN: toxic epidermal necrolysis ranging from skin scarring and eruptive melano-
TNF: tumor necrosis factor cytic nevi to vulvovaginal stenosis and dyspareu-
nia.13-19 Ocular lesions are the most common
complication of TEN, described in 20% to 79% of
a burn unit, and greater total BSA involvement. A patients,14,20-22 and include dry eye syndrome,
SCORTEN score between 3 and 6 and a delay of photophobia, a sandy sensation in the eye, sym-
[5 days before admission to a burn unit were found blepharon, corneal scarring, corneal neovascular-
to be independent predictors of mortality. A SCORTEN ization, corneal xerosis, trichiasis, reduced visual
of 3 to 6 carried a median survival of 7 months acuity, blindness, and subconjunctival fibrosis
after discharge and a 28% 2-year survival rate versus (Fig 2).3,13,23-25 Dry eye syndrome is the most
a 92% 2-year survival rate for a SCORTEN of 0 to 2, common ocular complication; it may even occur
while a [5-day delay in admission to a burn unit in patients who do not experience acute ocular
carried a median survival of 18 months and a 2-year involvement.26-28 The frequency of ophthalmic
survival of 42% versus an 89% 2-year survival with dysfunction during and after TEN necessitates
admission to a burn unit \5 days after the onset of that early ophthalmologic consultation be per-
TEN.9 formed in all cases.
Valeyrie-Allanore et al10 analyzed the histologic Dyspigmentation is common after TEN, with both
features of TEN, dermal infiltrate density, and hyperpigmentation and hypopigmentation seen,
severity of epidermal necrosis as possible predic- and may take years to improve.2,25 Other cutaneous
tors of mortality. No histopathologic findings, sequelae include scarring, onycholysis and onycho-
including dermal infiltrate density and full- dystrophy, which usually resolve within several
thickness epidermal necrosis, correlated with in- months, and the loss of fingernails, diffuse thinning
creased mortality during the initial hospitalization. of scalp hair, and pruritus.3,14,20,25 Upon prompt
However, once the univariate analysis was adjusted transfer to a special unit, careful removal of the
using the day 1 SCORTEN value, the association devitalized epidermis and covering the denuded
was no longer significant.10 areas with biologic biosynthetic, silver, or antibiotic
Yeong et al11 reported that the serum bicarbonate impregnated dressings should expedite the re-epi-
level was the most important marker in predicting thelialization process.29,30
mortality in patients with TEN. Regression analysis Dental complications in TEN include oral discom-
conducted on patients with TEN with epidermal fort, xerostomia, reduced mean saliva flow, in-
detachment [30% of the BSA (mean, 66.3% of BSA) creased saliva acidity, periodontal disease, gingival
found that the overall mortality rate was 40 times inflammation, and synechiae. A study of 16 patients
higher in those with serum bicarbonate level \20 with TEN found dry eye syndrome and persistent
mmol/L (P = .128).11 Ducic et al12 devised the dental abnormalities in all patients, suggesting that

From Dermatology, Preventive Medicine, and Pathology, Rutgers
University New Jersey Medical School, Newark.
Dr McDonough is currently affiliated with Dermatology, University
of Texas Southwestern Medical School, Dallas, Texas.
Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Robert A. Schwartz, MD, MPH, DSc (Hon),
FRCP (Edin), Professor & Head, Dermatology, Rutgers
University New Jersey Medical School, Medical Science
Bldg H-576, 185 S Orange Ave, Newark, NJ 07103-2714.
E-mail: roschwar@cal.berkeley.edu.
0190-9622/$36.00
187.e4 Schwartz, McDonough, and Lee
Fig 1. Toxic epidermal necrosis. Palmar involvement.
Table I. Severity of illness score for toxic epidermal
necrolysis*
Criteria: 1 point per condition
Age [40 years
Heart rate [120 beats per minute
Comorbid malignancy
Epidermal detachment [10% body surface area on day 1
Blood urea nitrogen [28 mg/dL
Glucose [252 mg/dL
Bicarbonate \20 mEq/L
Total score (mortality rate)
0-1 (3.2%)
2 (12.2%)
3 (35.5%)
4 (58.3%)
$ 5 (90.0%)
*Data from Bastuji-Garin et al.4
frequent teeth cleaning should be part of the long-
term treatment for TEN.31
Genitourinary problems are also observed after
TEN, including dyspareunia, adhesions, and introital
stenosis. One study found that vaginal synechiae
were often not identified until months after TEN
occurred, prompting the recommendation for early
gynecologic examination in all female patients with
TEN.18 Regular manual lysis of adhesion should be
performed. Erosive balanitis and urethral erosions
may be observed in male patients, prompting early
urology consultation. Phimosis is common after TEN
in male patients.13,32
Pulmonary disease has also been found after TEN,
with 1 study reporting a decrease in carbon monoxide
diffusing capacity in 3 of 4 patients 12 to 17 months
after discharge.33 Chronic pulmonary sequelae in-
clude chronic bronchitis, bronchiectasis, bronchiolitis
obliterans, bronchiolitis obliterans, organizing pneu-
monia, and respiratory tract obstruction.34
Less common complications from TEN include
esophageal stricture, nasal septal synechiae, and
severe oral fibrosis, resulting in difficulty eating and
speaking.25,35,36
J AM ACAD DERMATOL
AUGUST 2013
DIAGNOSIS
d Early toxic epidermal necrolysis can resem-
ble nonspecific drug reactions characterized
by a morbilliform eruption
d Epidermal necrosis seen histologically on
frozen sections has a high sensitivity and
low specificity for diagnosing toxic epider-
mal necrolysis
d Although not readily available at this time,
granulysin and high-mobility group protein
B1 levels are emerging tests that may provide
useful diagnostic information in the future
The diagnosis of TEN is made on the basis of both
clinical and histologic findings (Table III). A prodrome
of cough, rhinorrhea, fever, anorexia, and malaise
precedes mucocutaneous manifestations.28 The major
clinical findings include erythema, dusky or viola-
ceous macules and morbilliform or atypical targetoid
lesions.37 These cutaneous lesions develop into bul-
lae, epidermal sloughing, and frank skin necrosis with
a gray hue involving\10% of the BSA for SJS,[30% of
the BSA for TEN, and 10% to 30% of the BSA for SJS/
TEN overlap. TEN spreads symmetrically from the face
and trunk to the extremities (Fig 3).28 There is oral,
ocular, and/or genital mucositis in [90% of patients
with SJS and nearly all patients with TEN.38,39 The skin
and mucosal erosions of irregular sizes and shape are
painful. The Nikolsky sign—a separation of the pap-
illary dermis from the basal layer upon gentle lateral
pressure—and the AsboeeHansen sign—a lateral
extension of bullae with pressure—are also seen in
patients with TEN (Fig 4).39
In the early stages of disease, TEN clinically
resembles more benign drug reactions, such as
erythema multiforme major (EMM) and exanthema-
tous drug eruptions. However, EMM, viewed as a
separate entity from the SJS/TEN spectrum,40 is a
mucocutaneous reaction that is characterized by
typical target lesions of at least 3 distinct zones with
well-defined borders and papular atypical
target lesions usually distributed acrally (Fig 5).
Epidermal exfoliation and bullae may develop, but
are limited to \10% of the BSA, with 1 study reveal-
ing the median extent of epidermal detachment to be
1% in EMM.41 In addition, SJS/TEN involves $ 2
mucosal sites in 17% to 71% of cases, most commonly
involving the oral mucosa. EMM is usually drug-
induced or caused by mycoplasma, whereas
erythema multiforme minor (EMm) is principally
associated with the herpes simplex virus.41,42 By
presenting with typical or atypical target lesions,
fever, and mucositis, EMM may mimic early TEN
before extensive epidermal exfoliation occurs.
J AM ACAD DERMATOL Schwartz, McDonough, and Lee 187.e5
VOLUME 69, NUMBER 2

Table II. Sequelae of toxic epidermal necrolysis*

Organ/system Complication
Integumentary system Dyspigmentation, eruptive melanocytic nevi,
onycholysis, onychodystrophy, loss of
fingernails, and hair thinning
Ocular Sicca syndrome, sandy sensation,
symblepharon, corneal scarring, corneal
xerosis, trichiasis, blindness, subconjunctival
fibrosis, and photophobia
Pulmonary Chronic bronchitis, bronchiectasis, bronchiolitis
obliterans, bronchiolitis obliterans organizing
pneumonia, and respiratory tract obstruction
Oral cavity Sicca syndrome, reduced salivary flow and pH,
periodontal disease, gingival inflammation,
synechiae, and oral discomfort
Genitourinary system Dyspareunia, adhesions, introital stenosis,
erosive vulvovaginitis or balanitis, urethral
erosions, and genitourinary strictures
Gastrointestinal system Esophageal strictures
Management
Prompt referral to specialized unit. Removal of
devitalized epidermis. Cover with
nonadherent dressing. Avoid frequent
dressing change which may impede re-
epithelization. Skin coverage treatment:
biologic, biosynthetic, silver, or antibiotic-
impregnated dressing. Active infection
surveillance via skin lesion culture every 48
hours; prophylactic antibiotic use not
indicated. Environmental temperature
control. Aseptic handling and sterile field
creation. Venous peripheral access away
from the affected areas.
Prompt ophthalmology consultation. Eye drops
every 2 hours. Use of lubricants and topical
antibiotics. Developing synechiae disrupted
via a blunt instrument. Gas permeable scleral
contact lens therapy. Amniotic membrane
transplantation for patients with cornea,
conjunctiva, or lid margin involvement.
Careful monitoring of respiratory function.
Supplemental oxygen as necessary. Initiate
intubation and mechanical ventilation if
trachea and bronchi are involved. Aerosols,
nebulized saline, bronchodilators, bronchial
aspiration, and physical therapy.
Early initiation of oral nutrition via nasogastric
tube. Frequent spraying with antiseptics.
Removal of oral crusts.
Urology consultation. Regular manual lysis to
minimize adhesions. Foley catheter to
maintain patency of urinary tract.
Early institution of enteral feeding. Careful
monitoring of nutritional status, fluid
balance, and electrolyte balance. Prevention
of stress ulcers.

*Data from multiple sources.3,12-33

papillary dermis appear in more advanced stages

Fig 2. Toxic epidermal necrosis with ocular involvement.
Early TEN histologically resembles EMM, dis-
playing scattered necrotic keratinocytes.43 Full
thickness epidermal necrosis, a subepidermal
split, and a scant inflammatory infiltrate in the
of TEN (Fig 6).44,45 Early TEN can also be
indistinguishable from erythematous drug erup-
tions, which are characterized by a morbilliform
eruption, consisting of fine, discrete macules and
papules that tend to coalesce.
Frozen sectioning of skin specimens has been
used to expedite the differentiation of TEN from
EMM before a bullous eruption or mucosal erosions
occur. In a study of 35 patients with the initial onset
of a drug eruption, frozen sections of targetoid and
purpuric lesions revealed that 9 contained epidermal
necrosis. Of these 9, 6 patients were later diagnosed
with TEN/SJS, while 3 patients were later diagnosed
with EMM. None of the 26 patients without epider-
mal necrosis was later diagnosed with TEN/SJS.
187.e6 Schwartz, McDonough, and Lee J AM ACAD DERMATOL
AUGUST 2013

Table III. Diagnostic features of toxic epidermal necrolysis*

Clinical features Histologic features
Constitutional symptoms: fever, malaise, anorexia, and Full thickness epidermal necrosis
pharyngitis
Erythematous, dusky, violaceous macules, morbilliform Subepidermal split, lymphocytic infiltrate at the
or atypical targetoid macules starting on the trunk and dermoepidermal junction, CD41 T cells in dermis, and
spreading distally; confluence on face, trunk, and CD81 T cells in epidemis
elsewhere: TEN [ SJS/TEN overlap [ SJS
Manifests in flaccid bullae, epidermal sloughing, and Endothelial apoptosis
necrosis with gray hue
Exfoliation of the epidermis involving 10% of body surface
area for SJS, 10-30% for SJS/TEN overlap, and [30% for
TEN
Oral, genital, and ocular mucositis in nearly all patients
Tender skin and painful mucosal erosions
Positive Nikolsky sign
Positive AsboeeHansen sign
Systemic symptoms always present in SJS/TEN overlap and
TEN
Respiratory tract epithelial involvement in 25% of patients
with TEN

SJS, StevenseJohnson syndrome; TEN, toxic epidermal necrolysis.

*Data from Hazin et al,27 Kamada et al,34 Sedghizadeh et al,35 and Edell et al.36

Fig 3. Toxic epidermal necrosis. Note the denudation of

Fig 5. Erythema multiforme. Classical typical target
epidermis in sheets and the widespread involvement of
lesions involving the extremities.
the right lower extremity.

Fig 6. Histologic features of toxic epidermal necrosis: full

Fig 4. Toxic epidermal necrosis. Intense bullae formation thickness epidermal necrosis, a subepidermal split, and
positive for the Nikolsky and AsboeeHansen signs. scant inflammatory infiltrate in the papillary dermis.
(Hematoxylineeosin stain; original magnification: 3100.)
Courtesy of W. Clark Lambert, MD, PhD.

These results imply that epidermal necrosis in early Interest in serum markers for the early detection
frozen sections has a high sensitivity and a low of TEN has resulted from studies on soluble Fas
specificity for detecting TEN.46 ligand,47 perforin/granzyme B,48 soluble CD40
J AM ACAD DERMATOL
VOLUME 69, NUMBER 2
ligand,49 and granulysin,50 with research on gran-
ulysin advancing the furthest toward developing a
clinically useful test. Fujita et al51 recently developed
an immunochromatographic assay that can detect
high levels ([10 ng/mL) of serum granulysin within
15 minutes. This test, when administered 2 to 4 days
before the erosion of mucocutaneous surfaces, was
shown to have a sensitivity of 80% and a specificity of
95.8% in detecting TEN/SJS when compared to
ordinary drug-induced skin reactions. Although this
work is promising, additional studies with larger
sample sizes need to be conducted in order to
confirm the efficacy of the test, which is currently
not commercially available in the United States; a
research or large commercial laboratory would have
to develop this assay.52
Nakajima et al53 recently examined serum high-
mobility group protein B1 (HMGB1) levels in 22
healthy subjects, 11 patients with maculopapular
drug eruptions, 12 patients with EM, and 13 patients
with SJS and/or TEN using an HMGB1 enzyme-linked
immunosorbent assay kit. Serum HMGB1 levels in
patients with SJS and/or TEN were consistently ele-
vated compared to other groups from day e7 to day
21; the sensitivity of the assay above the threshold
level was 45.4%. Although the current role of HMGB1
in the pathogenesis of SJS/TEN is currently unknown,
strong positive staining of HMGB1 in necrotic kerat-
inocytes of SJS patients has been confirmed using
diaminobenzidine staining and immunohistochemi-
cal analysis. In contrast to granulysin and Fas ligand,
the persistent elevation of HMGB1 levels even after
cutaneous manifestations reduces the possibility of
false negative results. The HMGB1 test, in combina-
tion with granulysin and/or Fas ligand ones, may
serve to be an effective diagnostic tool. The HMGB1
enzyme-linked immunosorbent assay kit is commer-
cially available for research purposes only.54
Similarly, alfa-defensins 1 to 3 in the blister fluid,
Bcl-2 expression in the dermal infiltrate, serum
lactate dehydrogenase level, thymus and activation
regulated chemokine (TARC), and glutathione-S-
transferase-pi expression were recently identified
as emerging markers of TEN and may aid in the
early detection of TEN in the future.55-59
DIFFERENTIAL DIAGNOSIS
d The differential diagnosis of toxic epidermal
necrolysis includes erythema multiforme
major, staphylococcal scalded skin syn-
drome, drug-induced linear immunoglobulin
A dermatosis, acute graft versus host disease,
acute generalized exanthematous pustulosis,
drug reaction with eosinophilia and systemic
Schwartz, McDonough, and Lee 187.e7
symptoms, and most commonly, a general-
ized morbilliform drug eruption
d A skin biopsy specimen is useful in distin-
guishing toxic epidermal necrolysis from
alternative diagnoses
Early presentation of TEN must be distinguished
from both EMm and EMM. Clinical features are
primarily used to make the distinction from TEN,
because histopathologic findings and even emerging
serologic tests usually do not permit distinction
between EMM and SJS/TEN. EMm and EMM are
characterized by classic typical target lesions and/or
raised atypical targetoid lesions that are predomi-
nantly located on the extremities. EMM usually
shows signs of epidermal exfoliation and bullae
formation to a far less extent compared with
SJS/TEN. Infectious agents, especially herpes sim-
plex virus, are the most frequent causes of EMm
instead of medications.60
Other diagnoses that can mimic TEN include
staphylococcal scalded skin syndrome, drug-
induced linear immunoglobulin A (IgA) dermatosis,
acute graft versus host disease (GVHD), and gener-
alized morbilliform drug eruption (Table IV).
Staphylococcal scalded skin syndrome (SSSS) is a
disease that is characterized by detachment within
the epidermal layer caused by exotoxins released by
Staphylococcus aureus.61 Although it is usually seen
in children, adults, particularly those that are immu-
nosuppressed or who have renal failure, can also be
affected.62 Clinically, SSSS can be differentiated from
TEN by the lack of mucous membrane involvement
and by superficial epidermal peeling, which is in
contrast to the full thickness denudation found in
TEN.63 Biopsy specimens revealing superficial blis-
tering confirm the SSSS clinical impression.64
Drug-induced linear IgA bullous dermatosis (Fig 7)
consists of tense bullae in annular or herpetiform
arrangement with or without mucositis.65-67 The dis-
ease usually occurs within 2 weeks of exposure to
vancomycin.68 Direct immunofluorescence studies
revealing linear deposits of IgA at the basement
membrane confirm the diagnosis.69 The importance
of obtaining immunofluorescence studies in patients
with symptoms that clinically resemble TEN has been
highlighted; the initial diagnosis of TEN may be
altered to linear IgA bullous dermatosis based upon
histopathology and immunofluorescence studies.70,71
Acute GVHD occurs in bone marrow and alloge-
neic hematopoietic stem cell transplant patients and
can be difficult to distinguish from TEN. Acute GVHD
usually occurs 2 weeks after hematopoietic stem cell
transplant and presents as a symmetric acral morbil-
liform and sometimes lichenoid eruption. A bullous
187.e8 Schwartz, McDonough, and Lee J AM ACAD DERMATOL
AUGUST 2013

Table IV. Differential diagnosis of toxic epidermal necrolysis*

Disease
Erythema multiforme minor
Erythema multiforme major
Staphylococcal scalded skin syndrome
Drug-induced linear IgA
Severe acute graft versus host disease
Acute generalized exanthematous
pustulosis
Type of differentiation from TEN
Clinical
Typical or atypical target lesions;
symmetric acral predominance; lack
of mucosal involvement; most
commonly caused by infections
Typical or atypical target lesions;
symmetric acral predominance;
most commonly caused by
infections; minimal epidermal
exfoliation and bullae
No mucositis and superficial
epidermal peeling
Rare mucositis and annular
distribution of bullae
Folliculocentric distribution of
eruption and acral to proximal
spread of bullae
Rare, nonerosive mucous membrane
involvement
Histologic
Clinical features facilitate distinction;
epidermal cell death far less
extensive
Clinical features facilitate distinction;
epidermal cell death far less
extensive; scattered necrotic
keratinocytes
Intraepidermal blistering
Direct immunofluorescence studies
reveal linear deposits of IgA along
the basement membrane
Indistinguishable from TEN
Intraepidermal pustules and focal
necrotic keratinocytes

IgA, Immunoglobulin A; TEN, toxic epidermal necrolysis.

*Data from multiple sources.52-62

Generalized morbilliform drug eruption is the

Fig 7. Drug-induced linear immunoglobulin A bullous
dermatosis. Tense bullae in an annular arrangement asso-
ciated with the use of vancomycin.
eruption can occur with oral and/or genital involve-
ment. Grade IV acute GVHD involves full thickness
epidermal necrosis and can histologically be identi-
cal to TEN.72 Features such as the acral to proximal
spread, the folliculocentric distribution of the early
eruption, and the volume of diarrhea and bilirubin
elevation may provide clues to distinguish severe
acute GVHD from TEN.63
Acute generalized exanthematous pustulosis is a
drug-induced reaction typically presenting with
fever, edematous erythema, and sterile pustules.
Nonerosive mucous membrane involvement can oc-
cur, as can blisters and target-like lesions. Histology,
showing intraepidermal pustules, papillary dermal
edema, and focal necrotic keratinocytes, differenti-
ates it from TEN.73
most common drug-related hypersensitivity reac-
tion, comprising 95% of all drug-related skin reac-
tions. The mucous membranes are not affected.
Histology reveals nonspecific findings, a perivascu-
lar infiltrate, and dermoepidermal interface changes
without keratinocyte necrosis.
Another acute rash that may resemble TEN is the
drug eruption with eosinophilia and systemic symp-
toms (DRESS) syndrome, which may be evident with
facial edema, a morbilliform rash, and even tense
bullae and lip erosions, but which lacks epidermal
sloughing in sheets.74 A biopsy specimen of DRESS
syndrome does not show full thickness epidermal
necrolysis and has a prominent rather than scant
inflammatory infiltrate.
PREVENTION
d Patients with a history of toxic epidermal
necrolysis must avoid potential offending
agents and any cross-reacting medications
d Genetic human leukocyte antigen testing
should be performed in patients of East
Asian descent before carbamazepine therapy
and for all patients before antiretroviral
abacavir therapy
Patients with a history of TEN/SJS must avoid
the offending agent and any cross-reacting medica-
tions (Table V). Carbamazepine, phenytoin, and
J AM ACAD DERMATOL
VOLUME 69, NUMBER 2
Table V. Common cross-reacting medications that
induce toxic epidermal necrolysis
Antiepileptic drugs
Carbamazepine
Phenytoin
Phenobarbital
Antibiotic sulfonamide drugs
Sulfamethoxazole
Sulfadiazine
Sulfapyridine
Sulfamethizole
b-Lactam antibiotics
Cephalosporins
Carbapenems
Penicillins
phenobarbital may cross react with one another.75
Patients with a history of TEN/SJS induced by an
aromatic anticonvulsant should avoid this class of
medications. However, there is no evidence of
cross-reactivity between aromatic anticonvulsants
and lamotrigine.76 A history of sulfonamide antibio-
ticeinduced TEN/SJS does not preclude the use of the
sulfonamide nonantibiotics, which do not contain the
arylamine moiety that is implicated in the drug
reaction.77 A study examining the cross-reactivity
via testing of the cytotoxicity of blister fluid cells
has revealed significant reactivity between sulfa-
methoxazole and 3 structurally similar antibacterial
sulfonamides (sulfadiazine, sulfapyridine, and
sulfamethizole). No cross-reactivity was observed
between sulfamethoxazole and other sulfonamide
medications: diuretics (hydrochlorothiazide),
hypoglycemic (glyburide, tolbutamide, and chlor-
propamide), and 2 antibacterial sulfonamides
(sulfasalazine and sulfisoxazole).78 b-Lactam antibi-
otics, including cephalosporins and carbapenems,
should be strictly avoided in any patient with a history
of TEN/SJS to any member of the b-lactam family.79
Because there is a strong association between
major histocompatibility complex I allotype and
TEN, genetic testing may be used to prevent the
administration of drugs to individuals at increased
risk for TEN. Chen et al80 investigated the efficacy of
screening Han Chinese patients for the human leu-
kocyte antigen (HLA)-B*1502 allotype before car-
bamazepine use. In their study, a cohort of 4855
patients who would have been prescribed carbam-
azepine was tested for the HLA-B*1502 allotype, and
only HLA-B*1502enegative patients were given car-
bamazepine, while the HLA-B*1502epositive pa-
tients received an alternative medication. After 2
months of follow up, none of the patients experi-
enced TEN/SJS, which was significantly lower
Schwartz, McDonough, and Lee 187.e9
than the 10 patients predicted by the historical
estimate. A double blind, prospective, randomized,
controlled trial revealed significantly lower drug
hypersensitivity reactions to abacavir in a cohort
that consisted of only HLA-B*5701enegative patients
compared with a control group whose HLA type was
unknown.81 The costebenefit analysis of HLA phar-
macogenetic screening indicates that the cost of SJS/
TEN treatment, hospitalization, and psychosocial/
medical sequelae outweighs the cost per test and the
expense of alternative drugs.82
In accordance with these studies, the US Food and
Drug Administration recommends that HLA-B1502
genotype testing be performed in most patients of
East Asian ancestry before receiving carbamaze-
pine.83 Clinicians should be aware of regional/ethnic
prevalence of HLA-B1502 allele (10-15% of patients
in China, Taiwan, the Philippines, Malaysia,
Indonesia, and Thailand; 2-4% of patients in South
Asia, including India; and \1% of patients in Korea
and Japan). Additional large-scale trials are required
to determine the cost effectiveness of HLA-B1502
genotyping in ethnicities with low prevalence.83,84
The US Food and Drug Administration recommends
that all patients be tested for HLA-B*5701 before
receiving abacavir.85
TREATMENT
d Primary treatment involves discontinuation
of suspect medication along with transfer to
an intensive care unit, burn center, or other
specialty unit, and supportive therapy
d Current literature does not convincingly
support use of any adjuvant systemic ther-
apy; accordingly, its utilization may or may
not be considered
Primary treatment for TEN consists of removal of
the offending agent along with transfer to an inten-
sive care, burn unit, or other specialty unit, and
supportive therapy. Minimizing the time between
the onset of cutaneous symptoms and the arrival at
the specialty unit is crucial for improving the poten-
tial for survival.86 Identification of the offending
agent can be difficult in patients in whom a number
of new medications have recently been started.
Although in vitro lymphocyte transformation testing
(LTT) had initially shown promising results in deter-
mining the causative agent in TEN when testing is
performed within 1 week of disease onset,87 a
subsequent study evaluating LTT in patients with
SJS/TEN secondary to lamotrigine has shown a low
rate of positive LTT during both the acute and
recovery phase, rendering the use of LTT in clinical
setting unconvincing.88 The frequently negative LTT
187.e10 Schwartz, McDonough, and Lee
results may be related to the poor proliferative
properties of CD81 T cells.89
Burn units are accustomed to handling patients
with extensive epidermal damage. The mortality rate
may be reduced with early transfer to a burn
unit,13,90,91 where supportive care can be focused
on maintenance and reconstitution of the barrier
function of the skin, fluid balance, the prevention of
ocular damage, and careful monitoring for and
treatment of infection.
Coverage of denuded skin has been achieved
through paraffin gauze, porcine xenografts, and
human allografts, and through newer methods,
including Biobrane (Bertek Pharmaceuticals; UDL
Laboratories, Rockford, IL), a skin substitute consist-
ing of a synthetic bilaminar membrane,92 and
Aquacel Ag (ConvaTec, Skillman, NJ), a moisture-
retentive hydrofiber dressing that releases silver
within the dressing.93 In a study comparing the
synthetic bilaminar membrane to antiseptic solution
and daily dressing changes in patients with TEN, the
synthetic membrane was shown to lead to less serum
protein loss, diminished pain, and decreased time to
mobilization.92 In patients with severe denudation
resistant to the autologous skin grafting and the re-
epithelialization process, the use of umbilical cord
mesenchymal stem cell transplantation may have a
role in improving the clinical outcome.94,95 The
clinical efficacy of mesenchymal stem cell transplan-
tation may be attribute to the immunomodulatory
effects of mesenchymal stem cells.96 Active surveil-
lance for infection may be performed via skin culture
every 48 hours. AWood’s lamp may be used to detect
the presence of Pseudomonas aeruginosa, which
fluoresces yellow-green.30 The use of prophylactic
antibiotics is not recommended.28 An environmental
temperature setting at 308C to 328C may counteract a
hypercatabolic state by reducing caloric losses through
the skin. Peripheral venous access should be obtained
away from the affected areas, while procedures should
be performed using sterile methods.
Ocular damage in TEN can be prevented by
continual lubrication of the eye, topical antibiotic
use, and lysis of adhesions,63 with more invasive
procedures, such as amniotic membrane transplan-
tation, reserved for patients with large areas of
epithelial sloughing involving the cornea, conjunc-
tiva, or lid margins, which indicates a higher risk for
serious ocular sequelae.97 Daily erythromycin and
corticosteroid eye drops along with lubricants are
recommended in order to minimize infection and
inflammation.27 Scleral contact lens therapy should
also be considered as part of visual rehabilitation of
refractory ocular surface disease, a possible sequelae
of SJS/TEN, and may minimize corneal epithelial
J AM ACAD DERMATOL
AUGUST 2013
defects, photophobia, and discomfort while optimiz-
ing visual acuity.28,98 Additional therapies that
may improve ocular lubrication and minimize in-
flammation include artificial tears, ophthalmic cyclo-
sporine, autologous serum eye drops, and moisture
chamber eyewear. Dental follow-up should be part
of the long-term treatment of TEN; frequent washing
with antiseptic spray should be performed on daily
basis. Removal of oral crusting should be done as
necessary.28 Careful monitoring of respiratory func-
tion with the prompt implementation of supplemen-
tal oxygen, intubation, and mechanical ventilation
should be initiated as necessary.28 Nebulized saline,
bronchodilators, and physical therapy may also be
used. Clinicians should be vigilant of the patient’s
fluid and electrolyte balance. The use of a Foley
catheter may aid in the prevention of urethral stric-
ture,28 but unnecessary catheterization should be
avoided to minimize the risk of infection. The
discontinuation of medications and supportive ther-
apy remain the criterion standard for TEN treatment,
while the use of adjuvant therapies has shown
equivocal outcomes.
Systemic therapy
Interest in intravenous immune globulin (IVIG) as
a treatment for TEN arose from research showing
that IVIG could inhibit in vitro FaseFasL mediated
keratinocyte apoptosis.99 Since this initial research,
many studies have investigated IVIG treatment, but
the results have been conflicting, some showing
benefit and others not, rendering firm conclusions
elusive. Several studies have reported decreased
mortality in patients with TEN treated with IVIG
(Table VI). These studies found survival rates of 88%,
94%, and 100% with total IVIG doses of 2.7, 4, and 3.4
g/kg, respectively.100-104 Despite these results, other
studies have found no mortality benefit with total
IVIG doses of 1.6 or 2.8 g/kg compared with
supportive therapy alone105,106 or with a total dose
of 2 g/kg of IVIG compared with the mortality
predicted by SCORTEN.107 In the largest study to
date on the treatment of TEN/SJS, a retrospective
analysis of patients in the European Study of Severe
Cutaneous Adverse Reactions (EuroSCAR), including
281 German and French patients treated with corti-
costeroids, IVIG, or supportive therapy alone, found
that 75 patients treated with an average total dose of
1.5 to 1.9 g/kg of IVIG did not have improved
mortality compared with the supportive therapy
alone group. Previous studies showing a beneficial
effect of IVIG may have been biased by the reliance
on physicians’ assessment of area of skin detach-
ment, which is often overestimated, and by the lack
of control groups for comparison.108 However, the
J AM ACAD DERMATOL Schwartz, McDonough, and Lee 187.e11
VOLUME 69, NUMBER 2

Table VI. Summary of studies investigating intravenous immunoglobulin in toxic epidermal necrolysis
No. of Average total Time from onset to Decreased
Study patients dose (g/kg) administration (days) Average BSA% mortality Comment
Prins et al100 48 2.8 6 45 Yes
Trent et al101 16 4 N/A 37 Yes
Al-Mutairi et al102 12 3.4 1.6 58 Yes
Mangla et al104 10 \0.5 3.1 67 Yes Patients were children
Bachot et al107 34 2 5 20 No
Stella et al103 23 2.8 6.8 17 Yes Combined with 1 g/day
corticosteroids
Yang et al111 12 2 N/A 27 No Combined with 1-1.5 mg/kg/day
corticosteroids
Brown et al105 45 1.6 9.2 57 No
Shortt et al106 16 2.8 4.5 65 No
Schneck et al108 75 1.5-1.9 N/A N/A No

BSA, Body surface area.

total dose of IVIG administered in the aforemen-
tioned retrospective analysis was lower than that of
the previous studies reporting a mortality benefit.109
In another retrospective study, 23 patients treated
with a total dose of 2.8 g/kg of IVIG plus 1 g per day
of corticosteroids were found to have no significant
difference in mortality compared with that predicted
by SCORTEN. A large difference was noted in mor-
tality between the group treated with IVIG and
corticosteroids and a comparison group comprised
of 8 patients treated with corticosteroids, low-dose
IVIG, or a combination of the two.110 Any conclusion
from these data about the benefit of IVIG is rendered
suspect, however, by the fact that the comparison
group had an unusually high mortality rate of 75%,
which was well above the SCORTEN-predicted mor-
tality of 35%. In another study of combination
therapy, 35 patients with TEN receiving 1 to 1.5
mg/kg of methylprednisolone and a total dose of 2 g/
kg of IVIG were found to have no improved mortal-
ity compared with SCORTEN.111 It is important to
recognize that the benefits of supportive care in TEN
may be confounding the reported efficacy of IVIG.112
The lack of consistency in TEN study designs
assessing disease severity, dose of IVIG, timing of
IVIG administration, and patient comorbidities ren-
ders comparison extremely difficult.
However, Huang et al113 conducted the first
metaanalysis on the efficacy of IVIG therapy in
TEN patients despite the heterogeneity between
studies; in adults, the high-dose IVIG group had a
significantly lower mortality rate compared to the
low-dose IVIG group. However, when a multivariate
logistic regression model, which adjusts for age, total
BSA involvement, and delay of treatment, was ap-
plied, the IVIG dose no longer correlated with
mortality. Future multicenter, randomized controlled
trials with a statistically significant number of patients
are warranted in order to obtain robust level of
evidence-based data and to better understand the
clinical benefit of IVIG in TEN.
Corticosteroids have been used in the treatment
of patients with TEN with mixed results.
Corticosteroids have been associated with an in-
crease in infection, duration of hospital stay, and
mortality,14,114 although more recent studies have
suggested a possible beneficial role.105,115 A retro-
spective analysis of the EuroSCAR study found a
decreased mortality in German but not French
patients treated with corticosteroids compared with
controls who received supportive therapy alone.105
A study investigating pulsed high-dose corticoste-
roids, in which 12 patients were treated with 100 mg
or 1.5 mg/kg of intravenous dexamethasone for 3
days, found a decreased mortality compared with
SCORTEN. Giving steroids early, in high doses, and for
short periods of time may avoid the negative impact on
wound healing and infection seen in other studies with
steroids.115 Despite these promising findings, another
study found no mortality benefit, when compared to
SCORTEN, in 45 patients receiving nonpulsed meth-
ylprednisolone at a starting dose of 1 to 1.5 mg/kg for
the treatment of TEN.111,116 A combination therapy of
1.5 mg/kg per day of methylprednisolone and 2 g/kg
IVIG resulted in higher survival rate at almost all the
levels of SCORTEN and earlier arrest of progression
compared to corticosteroid monotherapy.117 A case
study has noted marked stabilization and rapid
clinical improvement in a 74-year-old patient with
TEN who was treated with another combination
therapy consisting of an intravenous bolus of 500 mg
methylprednisolone, 5 mg/kg infliximab, and 2 g/kg
IVIG over a 5-day span.118 There is no consensus on
the use of steroids in patients with TEN.
Other adjuvant therapies have been tried in TEN,
with scant supporting data. Plasmapheresis has been
187.e12 Schwartz, McDonough, and Lee
used in patients with TEN that are refractory to
supportive therapy and corticosteroids119 and has
been reported to provide rapid and dramatic im-
provement.119-123 In another study, 4 patients with
TEN with[80% BSA involvement who were resistant
to systemic corticosteroids, IVIGs, or supportive
therapy revealed cessation of TEN progression and
re-epithelialization after 3 to 8 plasmapheresis ses-
sions.124 A comparison of plasmapheresis to pulsed
high-dose corticosteroids in patients with TEN found
a more rapid improvement in the 2 patients treated
with plasmapheresis and a greater decrease in the
serum levels of intereukin-6, interleukin-8, and tu-
mor necrosis factorealfa (TNF-a), prompting spec-
ulation that the benefit of plasmapheresis might be
mediated through the removal of proinflammatory
cytokines.117
TNF-a inhibitors, granulocyte colony-stimulating
factor (GCSF), N-acetylcysteine (NAC), and cyclo-
sporine have also been used in therapy for patients
with TEN. Although a prospective trial using thalid-
omide, which has some TNF-a inhibitor activity, was
suspended because of increased mortality in the
treatment group,125 subsequent case reports have
emerged showing successful outcomes in patients
with TEN treated with the TNF-a inhibitors inflix-
imab,126,127 and etanercept128 with pentoxiphylline,
a medication with anti-TNF properties.129 GCSF has
been reported to be beneficial in patients with severe
TEN and neutropenia.130,131 Recently, de Sica-
Chapman et al,131 after reporting dramatic re-epithe-
lialization in the patients with severe TEN and
neutropenia treated with GCSF, suggested that
GCSF should be given to patients with severe TEN
with or without neutropenia.
Few previous studies have shown potential ben-
efits of NAC in treatment of TEN.132 Saavedra et al133
administered 600 mg of intravenous NAC every 8
hours in a patient with 75% BSA involvement who
initially did not respond to 3 g/kg of IVIG in a span of
3 days.133 The patient immediately improved in 48
hours and was discharged in 16 days with complete
re-epithelialization. Additional studies will be
needed to confirm the efficacy of NAC.
Interest in cyclosporine, a calcineurin inhibitor
that can block the function of T cells, has increased
with the discovery of the importance of granulysin in
the apoptosis in TEN. A recent study including 29
patients treated with cyclosporine for at least 10 days
found rapid cessation of disease progression and no
mortality.134 In addition, cyclosporine was well tol-
erated in most patients, with no increase in the rate of
infection. This study, along with another in which no
mortality was noted in 11 patients with TEN treated
with cyclosporine,135 supports a potential role for
J AM ACAD DERMATOL
AUGUST 2013
cyclosporine in the treatment of TEN. Again, addi-
tional studies will be needed to validate the efficacy
of cyclosporine. The treatment of TEN should focus
on discontinuation of the offending drug along with
early transfer to the intensive care unit, burn center,
or other specialty unit, and immediate supportive
therapy. Studies investigating adjuvant therapies
have not used standard dosing or time of initiation
and have shown inconsistent benefit compared with
SCORTEN. Given the recent findings on the impor-
tance of granulysin in the pathogenesis of apoptosis,
future pharmacologic investigation should focus on
therapies that decrease CD81 cell activation and
proliferation, while inhibition of the FaseFasL
apoptotic pathway should be a secondary goal.
CONCLUSION
Treatment of TEN involves discontinuation of the
drug, transfer to a specialized unit, such as an
intensive care unit or burn unit, and supportive
care, with no as yet convincing role for adjuvant
therapies. With both supportive care and adjuvant
therapies, early intervention is key. The recent
development of a possibly clinically useful test for
diagnosing early stage TEN is promising. HLA gen-
otype testing to prevent the administration of drugs
to susceptible individuals has proven to be an
important tool in the prevention of TEN and offers
an opportunity to decrease the number of deaths
associated with this deadly condition. Future re-
search on TEN should focus on the possible role of
adjuvant therapies, including timing and dosing, in
order to establish a standard treatment protocol.
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