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REVIEW
Anaesthesiology Intensive Therapy
2015, vol. 47, no 3, 257–262
ISSN 0209–1712
10.5603/AIT.2015.0037
www.ait.viamedica.pl
Toxic epidermal necrolysis
Joanna Hinc-Kasprzyk, Agnieszka Polak-Krzemińska, Irena Ożóg-Zabolska
Department of Paediatric Anaesthesiology and Intensive Therapy, COPERNICUS LLC, Gdańsk, Poland
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), also known as Lyell’s syndrome, are rare,
life-threatening diseases that are characterised by extensive epidermal detachment, erosion of mucous membranes
and severe systemic symptoms. In the majority of cases, the development of symptoms can be attributed to the
use of drugs; therefore, the disease pathology is thought to be caused by a severe adverse reaction to drugs. The
high mortality rate results primarily from the development of complications in the form of systemic infections and
multiple organ failure. TEN and SJS affect all age groups, including newborns, infants and older children. The rarity
of these syndromes has not permitted large, randomised studies, which has resulted in numerous difficulties in their
diagnosis and management. Because the pathogenesis has not yet been established, the management and systemic
treatment of these syndromes have not been standardised. The efficacy of the treatment options suggested has not
been confirmed by clinical studies involving suitably large groups of patients, especially children.
Key words: intensive care, children; toxic epidermal necrolysis, pathogenesis, toxic epidermal necrolysis, treatment,
Stevens-Johnson syndrome
Anaesthesiology Intensive Therapy 2015, vol. 47, no 3, 257–262
Stevens-Johnson syndrome (SJS) was first described in
1922 by Stevens and Johnson [1] in two children as acute
fever with skin eruptions and stomatitis. The term “toxic
epidermal necrolysis” (TEN) was suggested in 1956 by Lyell
when he observed toxic skin lesions resembling scalding
in 4 patients [2]; hence, this disease is also known as Lyell`s
syndrome. Bastuji-Garin [3] noted the overlap between SJS
and TEN in terms of their clinical, aetiological and histopathologic features. She recognised that both syndromes
are variants of the same disease that vary in the extent of
the skin lesions and thus suggested new definitions. Accordingly, SJS is diagnosed when the epidermal detachment
involves less than 10% of the body surface area; SJS/TEN
overlap is diagnosed when 10−30% is affected; and TEN
is diagnosed when more than 30% of the body surface is
affected (3.40).
The incidence of SJS is 1.2–6 cases, and that of TEN
0.4−1.9 per million individuals per year [5−7]. The estimated incidence of all three forms, i.e., SJS, SJS/TEN
overlap and TEN, is 2−7 per million per year. Three-fold
higher incidence rates are observed in HIV carriers, i.e.,
1 × 10-3 [8]. Moreover, the incidence of SJS/TEN increases with age and the coexistence of other ailments. This
syndrome is associated with reduced immunity and the
administration of numerous drugs, which can lead to
drug interactions and, ultimately, to the development
of adverse post-drug reactions.
The mortality rate of SJS/TEN was initially extremely
high, particularly for TEN, ranging from 25 to 70% [9]. Advances in maintenance treatment and the early admission
of patients to burn care departments or ICUs contributed to
a reduction of the mortality rate to 1−5% for SJS and 25−30%
for TEN [10, 11]. The mortality rates in the paediatric population are substantially lower. In their comparative analysis,
Levi and co-workers [12] studied 80 affected patients and
216 controls, all of whom were under 15 years of age. The
mortality in this group was 7.5%. Similar mortality rates in
the paediatric population were observed in studies based
on case series. According to Spies and colleagues [13] and
Ferrandiz–Pulido and colleagues (14), the mortality was
7%; Finkelstein and co-workers [15] found it to be even
lower, i.e., 2%.
AETIOLOGY
In the majority of cases, SJS/TEN are caused by medications or, to a lesser degree, by infectious factors. Based on
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their 10-year experience with the treatment of SJS/TEN in
children, Forman and colleagues [16] demonstrated that
SJS was induced by drugs in 91% of cases and by infectious
agents in 4.5% but that TEN was caused exclusively by drugs.
The findings of numerous studies have revealed a correlation between SJS/TEN and over 200 different drugs,
with the high-risk group including sulphonamides (cotrimoxazole, sulfasalazine), anticonvulsants (lamotrigine, carbamazepine, phenobarbital, phenytoin) as well as allopurinol, nevirapine and non-steroidal anti-inflammatory drugs
(NSAIDs) of the oxicam group, aminopenicillins, cephalosporins and quinolones [17]. The studies primarily involved
adults. Considering the differences between adults and
children regarding the types of drugs administered, some
authors have confirmed the list of drugs in children. According to Levi and colleagues [12], the high-risk group included
sulphonamides and anticonvulsants. A substantial risk was
also found to be associated with valproic acid, NSAIDs and
paracetamol. No cases caused by allopurinol, nevirapine or
oxicam were observed. Forman and colleagues [16] demonstrated a correlation between SJS/TEN sulphonamides
and both penicillins and cephalosporins. Similar results
regarding children were reported by Spanish authors [14].
In their study, the most common causes of SJS/TEN were
anticonvulsants (carbamazepine, lamotrigine, phenytoin),
followed by antibiotics (penicillins, macrolides) and NSAIDs,
except for oxicam. Of note, the substantial-risk group contained paracetamol. Several reports have described cases
of SJS/TEN following the use of paracetamol [18]. The study
involving 32 paediatric patients additionally showed that
ibuprofen significantly worsened the course of disease and
increased the risk of complications [19].
The infectious agents associated with SJS/TEN in the
paediatric population predominantly include Mycoplasma
pneumoniae, viruses (influenza, Epstein-Barr, herpes 6 and 7,
cytomegaloviruses, parvoviruses, coxsackie viruses), bacteria (β-haemolytic streptococci), mycobacteria and rickettsia
[20]. However, it has not been demonstrated whether infectious agents directly cause SJS/TEN or are cofactors when
combined with drugs. The infectious aetiology of SJS/TEN
can be suspected when the infection preceded the skin
lesions by 1 week and/or the titre of IgM antibodies can be
determined. In contrast, a correlation between the development of disease and drug use suggests that a new drug
was added 1-8 weeks prior to the appearance of the skin
lesions. Generally, the average time between the administration of drugs and the occurrence of symptoms ranges from
6 days to 2 weeks [21].
IMMUNOPATHOGENESIS
The pathogenesis of SJS/TEN has not been elucidated
and is the subject of numerous studies. The detachment of
258
the epidermis in TEN is caused by the necrosis of keratinocytes following apoptosis [22]. The cells responsible for apoptosis are CD8+ T lymphocytes [23]. The exposure to a drug
induces their maturation into cytotoxic T lymphocytes. Two
theories exist regarding their mechanism of activation. The
first theory is based on the pharmacological interaction of
the drug and the immune system. According to this theory,
the drug stimulates the immune system via non-covalent
binding directly with the major histocompatibility complex
I (MHC) and T cell receptors. The second theory, based on
the pro-hapten/hapten reaction, states that drug metabolites bind covalently to cell proteins, which leads to the
formation of molecules capable of stimulating the immune
system [21, 24].
Many factors have been implicated to be responsible
for keratinocytes apoptosis, and granulysin is currently considered the main cause. Chung and colleagues [25] found
two- to four-fold higher concentrations of granulysin in the
blister fluid compared with the concentrations of perforin,
granzyme B and soluble Fas ligand. Additionally, a correlation between the concentration of granulysin in the blister
fluid and the severity of disease has been demonstrated [24].
Fas ligand, another factor involved in apoptosis, is a transmembrane protein that is found in the cell membranes of
cytotoxic T lymphocytes, NK cells and keratinocytes and
can be detached from the cell membrane surface into its
soluble form (sFasL) [26, 27].
Moreover, granzyme B and perforin are considered to
be apoptotic factors in TEN. They are secreted together with
granulysin by activated T lymphocytes. The role of TNF-α in
the pathogenesis of TEN is also being investigated. Its concentration in the blister fluid, skin and serum of TEN patients
has been found to be increased [21]. Viard-Leveugle and
colleagues [28] emphasised the involvement of nitric oxide
(NO) in apoptosis. TNF-α and INF-γ secreted by activated T
cells increase the expression and activity of induced NO
synthetase (iNOS) in keratinocytes. Increasing levels of NO
result in the increased expression of FasL in keratinocytes
and lead to Fas- and caspase 8-mediated cell death.
DIAGNOSIS
In many cases, it is extremely difficult to identify which
particular drug is responsible for SJS/TEN because individual
patients may take many medications. Therefore, diagnostic
tests are being developed that would facilitate the identification of a harmful agent.
In 2010, an algorithm of drug causality for epidermal
necrolysis (ALDEN) was suggested [29]. The results of ALDEN
were found to be consistent with those of the EuroSCAR
study.
Because the course of disease of SJS/TEN is severe, tests with
the subcutaneous administration of the drug that is suspected
Joanna Hinc-Kasprzyk et al., Toxic epidermal necrolysis
of inducing symptoms and with re-exposure to the drug are not
recommended [11]. Epidermal patch tests are suggested [30],
but their sensitivity for SJS/TEN is low. At present, ex vivo/in vitro
testing is being evaluated. The lymphocyte transformation test
(LTT), which measures the in vivo transformation of T lymphocytes induced by the drug, shows a sensitivity of 60−70% in
patients who are allergic to β-lactam antibiotics; however, in
the case of SJS/TEN, its sensitivity is markedly lower [11, 31].
Another in vitro test is based on an increase in the expression
of CD69 antigen on T lymphocytes two days after stimulation
with the drug, which indicates hypersensitivity to the drug.
Furthermore, the use of immunochromatographic analysis
has been suggested, which enables the detection of high
concentrations of granulysin in serum. When used 2−4 days
before the occurrence of mucous membrane erosion, it
shows a sensitivity of 80% and a specificity of 95.8% [32].
All of the tests mentioned above require further studies to
determine their usefulness for the diagnosis of SJS/TEN.
When an infectious aetiology is suspected, serological
tests are needed to determine the IgM and IgG titres. In
addition, the polymerase chain reaction (PCR) method is
recommended for the diagnosis of herpes simplex virus,
varicella, Epstein-Barr virus, herpes 6 and 7 viruses, parvoviruses and Mycoplasma pneumoniae [20].
CLINICAL SYMPTOMS
Generally, the development of SJS/TEN is preceded by
non-characteristic prodromal symptoms, such as pharyngitis, fever, apathy, headaches, eye itch or dysphagia, which
occur approximately 1−10 days before the appearance of
the main disease symptoms [20, 21].
The variability and dynamics of the presentation in
children and in adults are similar. The skin lesions are initially located on the face and trunk, assuming the form of
red spots and papules merging into generalised erythema
multiforme. Subsequently, blisters filled with serous fluid develop that exfoliate leaving ulcerations with areas of necrosis
and bleeding, painful erosions and finally crusts. The above
process gradually affects an increasingly large area of skin
and mucous membrane (though rarely in small children).
The presence of the Nikolsky`s sign, i.e., apparently normal
epidermis exfoliating when slightly rubbed, can suggest
toxic epidermal necrolysis [20].
Acute injuries to the skin and mucous membranes are
accompanied by symptoms in other organs: conjunctival
ulceration with purulent inflammation, painful inflammatory ulcerated lesions in the airway, gastrointestinal tract
and sexual organs that manifest as bleeding and evidence
of infection [14].
As TEN progresses, patients are likely to develop respiratory failure in the course of pneumonia or pulmonary
oedema, acute renal injury most likely from cytokine-
-induced injuries to proximal tubules and the glomerular
filtration system. In addition, sepsis, liver failure or myocarditis can develop [14, 21].
DIFFERENTIAL DIAGNOSIS
With regard to the dermatologic symptoms, SJS/TEN
should be differentiated from erythema multiforme, staphylococcal scalded skin syndrome (SSSS), linear IgA bullous
dermatosis, graft-versus-host disease (GVHD), acute generalised exanthematous pustulosis (AGEP), drug rash with
eosinophilia and systemic symptoms (DRESS), generalised
measles-like drug rash and pemphigus vulgaris or paraneoplastic pemphigus [32].
PREVENTION
Patients with a history suggestive of SJS/TEN should
avoid high-risk medications. Attention should be paid to
possible cross-reactivity of certain drug groups, e.g., anticonvulsants [32].
Numerous studies indicate genetic predispositions to
drug hypersensitivity reactions, which are strongly associated with the major histocompatibility complex. Studies of
the Han population have demonstrated a 100% correlation
between human leukocyte antigen (HLA)-B*1502 and hypersensitivity to carbamazepine as well as HLA-B*5801 and
allopurinol. A correlation between HLA-B* 1502 and carbamazepine has not been confirmed in the European population; however, the correlation between HLA-B*5801 and
allopurinol was found to be weaker in the European population than found in Asian studies, i.e., 61%. The other correlations observed in the European population concerned
HLA-B*5701 vs. abacavir and HLA-B*3101 vs. carbamazepines [21, 24, 33, 34].
Genetic tests performed before the use of drugs can prevent SJS/TEN in some groups of patients. The Food and Drug
Administration (FDA) recommends the HLA-B*1502 test
in patients of East Asian origin before the administration
of carbamazepine and the HLA-*5701 test in all patients
prescribed abacavir [32].
TREATMENT
No consensus standard treatment, particularly in children, has been established for SJS/TEN, which reflects the
small number of patients studied [9, 20, 35]. An essential
issue underscored in the literature is the need for early, rapid
diagnosis, withdrawal of the causative agent inducing the
inflammatory reaction, implementation of treatment and
transfer of patients to specialised centres, which have been
shown to decrease the incidence of complications and mortality rates [20]. To achieve a good therapeutic outcome, the
cooperation of the team of specialists is essential. Local treatment of skin lesions involves surgical debridement under
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general anaesthesia, the application of biological and biosynthetic dressings acting as a protective barrier and steroid
and antibiotic ointments [32]. The recommended management includes intensive care with provision for central vascular accesses, invasive monitoring of vital functions, fully
aseptic conditions, prevention of eye injuries, monitoring of
infections, pain management, sedation, respiratory support,
maintenance of fluid balance, parenteral nutrition covering
increased energy requirements, and maintenance of optimal
room temperature, i.e., 30−32°C. Fluid requirements fulfilled
by the supply of compound electrolyte solution (CES) was
determined at 2 mL kg-1 % of affected body surface-1 or CES,
0.7 mL kg-1 % of affected body surface-1 plus 5% albumin
solution in the amount of 1 mL kg-1 % of affected body surface-1 (according to Mockenhaupt). Antibiotic prophylaxis
is not recommended; if an infection develops, targeted
therapy is advised [20, 24, 32].
There is no gold standard for the treatment of the underlying pathology; two therapies of SJS/TEN in children
are widely accepted, although both arouse controversy.
The therapies used most commonly are intravenous
immunoglobulins (IVIGs) and corticosteroid pulses [11, 24,
36]. By blocking Fas receptors, IVIGs inhibit the apoptosis
of keratinocytes. IVIGs in a dose of 2−4 g kg-1 administered
during the first 4 days have been reported to inhibit the
evolution of skin lesions, shorten the disease duration and
improve the survival rates [20]. However, other studies did
not confirm the above findings [11, 37]. The role of corticosteroid therapy is also being disputed. According to some
studies, the therapy results in good outcomes only when
corticosteroids are administered in large doses during the
first days of the disease; moreover, the risk of complications
in cases of prolonged use of these drugs has been emphasised [9, 20]. Completely different opinions have also been
reported. For instance, according to Chave [38], corticosteroids can be harmful (increased risk of sepsis and increased
mortality), are ineffective and should not be recommended
for the treatment of TEN.
The second-line drugs and therapies include cyclosporine, infliximab and plasmapheresis used in various
combinations. Cyclosporine, an immunosuppressant, has
been used to treat SJS/TEN for several years and is associated with good outcomes, i.e., the rapid re-epithelialisation
of the skin. It inhibits the immune responses mediated by T
lymphocytes, macrophages and keratinocytes and affects
the production of inflammatory mediators. Modifications of
the doses and duration of treatment can reduce the risk of
side effects, which are lower than those incurred by cyclophosphamide or thalidomide. However, the development
of complications should be taken seriously, e.g., kidney
dysfunction, neutropaenia or leukodystrophy; monitoring
the serum drug concentrations is thus required [11, 32, 39].
260
Another immunosuppressive and immunomodulatory
preparation is infliximab, which most likely blocks the apoptotic effects of TNF-α [40]. Infliximab is also used to treat
other immunological diseases and is being tested in larger
populations of patients [41, 42].
Finally, plasmapheresis has also been applied to treat
SJS/TEN and has resulted in good outcomes in both adults
and children [11, 20, 43, 44]. Generally, it is used after pharmacological therapy (IVIGs and corticosteroids) when lesions progress or when there is no improvement in the
patient’s condition.
The treatment and recovery usually last several weeks or
longer and late complications can develop [45]. According
to Ferrandiz-Pulido [14, 20], late complications occur in approximately 29% of cases and include skin discolouration,
nail deformities, chronic ulcerations of the oral cavity and
sexual organs, lingual papilla atrophy, photophobia, dry
conjunctivitis, conjunctival adhesions, impaired growth of
lashes, and blindness. Finkelstein [15] assessed the incidence of late complications at 47%. In the majority of cases,
skin discolouration and scars (42%) as well as various types
of vision impairment (27%) are observed; the remaining
ones include phimosis, bronchitis, cholangitis and venous
thrombosis.
PROGNOSIS
In 2000, Bastuji-Garin and co-workers [46] suggested using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale
to evaluate the risk of death among patients with SJS/TEN
admitted to specialised departments. Seven independent
death risk factors were established; based on these risk factors, a severity-of-illness scale and predicted mortality rates
were determined (Table 1).
Table 1. The SCORTEN scale (according to [46])
Risk factor: score of 1 each
Age > 40 years
Heart rate > 120 min-1
Concomitant malignant neoplasm
Epidermal detachment > 10% of body surface
Serum urea level > 10 mmol L-1
Serum levels of bicarbonates < 20 mmol L-1
Serum levels of glucose > 14 mmol L-1
Mortality rates — scores
0−1 — 3.2%
2 — 12.2%
3 — 35.5%
4 — 58.3%
> 5 — 90.0%
Joanna Hinc-Kasprzyk et al., Toxic epidermal necrolysis
To achieve a higher accuracy, the assessment should be
performed on post-ICU admission day 1 and 3 [47].
The SCORTEN scale was formulated based on adult
populations; hence, its usefulness for paediatric patients requires further study. According to Hamilton and colleagues
[35], better prognostic factors of mortality in the paediatric
population are the pediatric index of mortality (PIM 2) and
pediatric logistic organ dysfunction (PELOD) commonly
used in paediatric ICUs.
With regard to prognosis, various indices of homeostasis
disorders are also being studied. Yeong and co-workers
[48] have demonstrated forty-fold higher mortality rates
in TEN patients with concentrations of bicarbonates lower
than 20 mmol L-1. Yun and colleagues [49] have suggested
the determinations of lactate dehydrogenase in the early
stages of SJS/TEN to evaluate the severity of disease. Furthermore, Ducic and co-workers have devised a formula
to calculate the mortality rates based on three risk factors
affecting the prognosis, i.e., symptoms of sepsis on admission, advanced age and the body surface area affected [32].
ACKNOWLEDGEMENTS
1. The authors declare no financial disclosure.
2. The authors declare no conflict of interest.
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Joanna Hinc-Kasprzyk, MD
Department of Paediatric Anaesthesiology
and Intensive Therapy, COPERNICUS LLC
ul. Nowe Ogrody 1−6, 80−803 Gdańsk, Poland
e-mail: [email protected]
Received: 1.06.2014
Accepted: 20.12.2014