TOXIC EPIDERMAL NECROLYSIS

TOXIC EPIDERMAL NECROLYSIS - LYELL’S SYNDROME
Cabral L., Riobom F., Diogo C., Teles L., Cruzeiro C.
Plastic Surgery and Burns Unit Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal
SUMMARY. Toxic epidermal necrolysis (Lyell’s syndrome) is a rare but very serious dermatological lesion characterized by the sudden onset of high fever, signs of systemic toxicity, and intense mucocutaneous exfoliation. Its pathophysiology is not yet well determined, although the presence of an immunological basis is almost consensual. It usually appears as a response to the taking of a drug and, in spite of being self-limited in the absence of complications,
it is associated if not well managed with high morbidity and high mortality due in most cases to the development of
sepsis. The main treatment is the immediate suspension of the inducing drug and early admission of the patient to a
hospital facility which is capable of providing intensive support care and minimizing the risk of infection and which also offers conditions for the performance of surgical debridement and the covering of the affected areas, i.e. a burns
unit. Several therapeutic measures designed to lower the morbidity and mortality of this syndrome are in the course
of study, including the use of plasmapheresis, the administration of high doses of N-acetylcysteine, immunosuppression, and hyperbaric oxygen. The treatment protocol in use at the Coimbra Burns Unit in Portugal is presented and
illustrated with three clinical cases from the Unit.
Introduction
Clinical presentation
Toxic epidermal necrolysis (TEN), also known as
Lyell’s syndrome, is a rare but extremely serious
nosological entity characterized by high fever, systemic toxicity symptoms, and extensive mucocutaneous exfoliation. It usually occurs in response to
certain drugs and accounts for approximately 1% of
all hospitalizations due to adverse drug reactions.
Some
apparentl y
idiopathi c
cases have been described and it can occur as a
graft-versus host reaction.
Although previously described by various researchers, TEN was rst made known in the medical
literature through the works of Alan Lyell, whose rst
article, a classic of its genre, was published in 1956
in the
.1 In that article,
the word “necrolysis” was proposed to describe the
isolated necrosis of the epidermal layer of the skin
and its detachment from the underlying dermis,
where there are practically none of the inammatory
changes usually present in toxic erythema conditions.
TEN can affect both infants and adults, but the onset is more frequent at extreme ages, i.e. before 5
years of age and after 64.2 Like other drug reactions,
it is more common in females, with a female/male ratio of 3:2 or even 2:1. No racial differences have been
described.
The incidence of TEN in the general population
varies from 1 to 1.3 cases per million people per year.
The mortality rate is very high, reaching 25 to 70%,
according to different sources. In recent years, many
works have demonstrated a reduction in the mortality
and morbidity of such patients treated in burns units.
Contact with the causative drug is followed by a
period of 1 to 45 days without any signs or symptoms (average, 14 days).3,4 TEN usually begins with
a prodromal phase, a u-like syndrome with fever,
rhinitis, cough, thoracic pain, myalgia, anorexia,
malaise, and asthenia. The rst skin and mucosal lesions that characterize the acute phase occur within
two or three days and may last for 2-12 days. Skin
involvement begins with itching, which is soon accompanied by a painful eruption on the face and upper trunk that extends to the rest of the body within a few days, though occurring primarily on the
trunk and proximal areas of the limbs. The initial skin
lesions are macular-type, with irregular outlines and
a darker centre, reaching a maximum extent within
another 2-3 days, depending on the drug’s half-life
(drugs with a longer half-life are generally associated with the onset of prolonged skin symptoms and
higher mortality).5 During this spreading stage, the
initial lesions rapidly develop into bullae lled with a
practically clear uid1 that forms large plaques of
necrotic epidermis, detaching from the underlying
dermis and resembling wet clothes, owing to wrinkling. Simultaneously, there is the presence of Nikolsky’s sign,6 a condition in which a slight rubbing pressure over apparently intact skin areas will cause the
epidermis to peel away easily.
Epidermal necrolysis may involve the whole body
except for the scalp, which is usually unaffected. Denuded areas present an exudative, dark-red dermis.
The loosening of the epidermal layer results in the discharge of body uids, proteins, and electrolytes which,
if not replaced, will lead to haemodynamic changes
with hypovolaemia and renal failure.
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Mucosal lesions usually occur prior to epidermal
necrosis and are characterized by erosion and sloughing of conjunctival, oropharyngeal, nasal, oesophageal,
urethral, anal, vaginal, and perineal mucosae, showing
a special predilection for the stratied pavement epithelium.7 The extent and location of the lesions is patient-specic, and mainly affects the conjunctival,
oropharyngeal, and urethral mucosae. The lesions are
very painful - mouth lesions may even impair the patients’ correct rehydration and nutrition, urethral lesions may induce urine retention, and conjunctival lesions frequently result in photophobia. The pain induced by mucosal and skin involvement often determines the administration of opioid analgesics.
During this period, fever remains high even in the
absence of infectious complications, which has been
attributed to the release of pyrogenic agents by the
necrotic epidermal tissue, particularly interleukin-1.
In the absence of complications, the recovery
phase generally lasts from one to three weeks, allowing for the re-epithelialization of the skin and mucosae. In TEN, the re-epithelialization process is usually faster than in second-degree burns of similar extent (which is understandable, since the dermal layer is not affected) and is even faster in areas not subject to pressure. The mucosae usually require a
longer re-epithelialization period than cutaneous areas. Fever may persist until complete healing, even
in the absence of infection.
Complications
Given the development phases mentioned above,
TEN can be considered a self-limiting disease which, if
without complications, would not have any sequelae.7
However, life-threatening complications are unfortunately the general rule, signicantly impairing the patient’s quality of life.
The most serious complication, often fatal, is infection. Sepsis is the main cause of death from TEN,8
accounting for over 50% of all fatal cases. Loss of
the skin barrier through epidermal sloughing allows
tissue invasion by exogenous and endogenous organisms. Unlike thermal lesions, in which the dermis
is also affected, inducing a transient reduction of local micro-organisms, the dermis remains intact,
though susceptible to penetration by micro-organisms that are unaffected by the pathological process
and grow freely within exudates and the necrotic epidermis. Cutaneous lesions are rst colonized by
, followed by Gram-negative
bacteria, particularly
; patients treated with broad-spectrum antibiotics or
corticosteroids may also develop a fungal infection,
mostly due to
. Disseminated intravascular coagulation may occur following sepsis
complications. Patients with central venous access
catheters show a higher incidence of bacteraemia
and sepsis.
Ocular complications are very frequent, ranging
from mild conjunctival hyperaemia to purulent conjunctivitis or even fusion of the eyelids and eyeballs
(ankylosymblepharon), leading to total blindness.
These complications are induced by the erosion and
desquamation of the conjunctiva and by subsequent brosis; some cases of corneal and lachrymal system
(lachrymal duct atrophy) lesions have been described.
Respiratory disorders are a common nding, leading to the necessity of articial ventilation in 10-20%
of the patients. Numerous factors may account for pulmonary function deterioration, such as shallow respiration due to pain, pulmonary oedema caused by increased alveolar-capillary permeability,9 and aspiration
of debris from sloughing of the oropharyngeal (and,
according to some researchers, of the tracheobronchial)10 mucosa, which may pave the way for bronchiolitis obliterans11 and pneumonia or even develop into the adult respiratory distress syndrome.12
Digestive tract involvement includes not only
oropharyngeal sloughing, as already referred to, but
also disseminated erosions at a more distal level,
particularly lesions in the oesophageal epithelium,
which are similar to peptic oesophagitis and may
lead to dysphagia and more rarely to increased gastric bleeding; a case of oesophageal rupture has
been described.13 Intestinal lesions are less frequent6,14
and may present as bloody diarrhoea. Although 50%
of patients show a moderate increase of liver
transaminase levels, approximately 10% may develop real hepatitis.6
Haematological disturbances are very common,15
particularly anaemia, which is usually normocytic and
normochromic and may be precipitated by several factors, including erythroblastopenia. Leukopenia is also
very common: lymphocytopenia occurs in 90% of all
patients owing to a transient depletion of CD4+ T-lymphocytes,16 and neutropenia is observed in 30% of cases, generally associated with the appearance of sepsis, which is an unfavourable prognostic sign.17 Thrombocytopenia is less frequent and occurs in 15% of patients.18
Other less frequent complications have also been
described, affecting the patient’s morbidity, such as
vaginal or urethral stenosis, transient alopecia, loss of
nails and eyebrows, keloid formation, and skin hypoor hyperpigmentation.19
Aetiology
As already said, although some researchers accept
that TEN may be idiopathic in origin, most cases present as an idiosyncratic response to the administration
of a certain medication or drug, irrespective of
dosage.20
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Among the series of medications described as being capable of causing TEN,3,21 those most often involved include sulphonamides (the commonest trigger
in adults,22 accounting for approximately one-third of
all cases),18 anti-epileptic drugs (particularly phenytoin,
the most frequent agent among children,19 carbamazepine, and phenobarbital), allopurinol, oral penicillins (ampicillin, amoxicillin), and non-steroidal antiinammatory agents with a prolonged half-life (especially those derived from pirazolone or oxicam).3,23 Several other drugs reported less commonly in the literature range from paracetamol to different antibiotics,
tuberculostatics,24 antifungal agents,25 cytostatics,26 and
vaccines.27 The risks associated with drugs responsible
for the onset of TEN are diverse, even among similar
drugs. It is also likely that TEN results from a synergic
activity between different drugs, or between some
drugs and other chemical agents that have been related to the disease, such as pesticides, fumigants,
herbs, and food additives.28
While some viral infections are thought to facilitate
the onset of TEN after the intake of the triggering
agents29 (from upper airway infections to the acquired
immune deciency syndrome), some researchers refer
to a frequent association with certain conditions,30 such
as systemic lupus erythematosus, leukaemia, lymphomas, graft-versus-host disease23 (in which cases the
TEN mortality rate reaches 100%), ulcerative colitis,
and Crohn’s disease. Other researchers suggest a genetic susceptibility associated with certain types of antigenic markers of the HLA system (B12, A29, DR7).20,31
Pathophysiology
The pathophysiology of TEN has not been fully
elucidated and it remains a subject of controversy.
The existence of an immunological-based mechanism,32
however, is practically consensual, given the amount
of clues in that direction.
The fact that the time between administration of
the triggering drug and the onset of the clinical picture is substantially reduced in cases of the syndrome’s rare recurrence (from 12-14 days to less than
2 days, or even to a few hours) strongly supports
the existence of primary sensitization and immunological memory. The linking of TEN to a series of autoimmune diseases, such as systemic lupus erythematosus, and the appearance of Sjörgen syndromes33
in surviving patients are relatively common.
Several cases have been reported of graft-versushost reactions in patients subjected to homologous
transplants.15
Accumulated evidence suggests that, unlike humoral toxicity mediated by auto-antibodies (the presence of which has seldom been described in cases
of TEN) or by the complement system, this is only a
cell-mediated cytotoxicity situation,15,18,34,35 where it has
92
been possible to establish the presence of mononuclear cells adjacent to necrotic keratinocytes and a
change in lymphocyte subsets of both peripheral blood
and inammatory cell inltrates32 (with CD4+ T-lymphocytes in the upper dermis layer and CD8+ lymphocytes in the epidermis and the dermo-epidermal
junction.36 Whatever its mode of action, this immunological response is certainly modulated by a number of factors, including a potential genetic predisposition31 (hence the association with some phenotypes of the HLA system). The possibility that a previous viral infection may trigger the whole process is
an issue to be considered.7,16
Another theory is that of a toxic effect by the
drug itself and/or by one of its metabolites,18 due to
its accumulation following a decient metabolization
that could be related to congenital or induced enzymatic changes. This argument is based on the relative lack of the above-mentioned cell inltrate compared to cases of general epidermal necrolysis, which
is not paralleled by similar situations of cell destruction, on a reduction in the N-acetylation capacity of
patients with TEN,37 and on the benecial effect of
plasmapheresis in the management of such patients.38
Diagnosis
Apart from the presence of the typical clinical
manifestations already mentioned (fever, extensive
and painful skin necrolysis resembling wet clothes, a
positive Nikolsky’s sign, oral and conjunctival sloughing, etc.), the conrmation of a TEN diagnosis includes the performance of a skin biopsy - the histological ndings reveal the actual vacuolization of the
basement membrane, the formation of subepithelial
bullae, and the necrosis of epidermal keratinocytes.39
While the analysis of a detached skin section reveals
only full-thickness epidermal necrosis, there is an alternative method of examining the base of a blister,
the so-called Tzanck preparation, which can reveal
the presence of eosinophils and basal cells with a
high nucleus/cytoplasma ratio.39
Differential diagnosis
Erythema multiforme (EM) and the Stevens-Johnson syndrome (SJS) are two skin disorders that share
some of the clinical features of TEN, making it sometimes confusing, or even controversial, to tell them
apart, particularly because it is not possible to clearly dene their histological differences.40 Some researchers go so far as to claim that they are not
three distinct disorders but instead variants of the
same nosological spectrum, with EM as the least serious form of the disease and TEN as the most lethal.
Chan et al.2 proposed some criteria to distinguish the
three situations: EM would thus be characterized by
the presence of localized lesions less than 3 cm wide;
it may or may not present as targets and cover less
than 20% of the body surface; and there may be an
absence of mucosal involvement or the involvement
of one single area, with minimum symptomatology.
In SJS, the initial lesions, which may or may not be
target-shaped, are also less than 3 cm wide but may
coalesce and involve between 10 and 20% of the
body surface; SJS always includes the involvement of
two or more mucosal surfaces and fever may be high.
In TEN, the affected area covers at least 20-30% of
the body surface, including non-exposed areas, presenting as large bullae over an erythematous base
that coalesces in large, easily detachable plaques (over
3 cm wide); fever is high and there is always mucosal involvement.
The skin infection caused by a certain strain of
(phage II, group 71), which
is responsible for the release of a specic exotoxin,35,41 may resemble scalded skin (staphylococcal
scalded skin syndrome [SSSS]); this is sometimes
misdiagnosed as TEN, despite being much more benign and showing a low mortality rate (0 to 27%,
according to sources). This syndrome is commonest
in neonates and children, but rare cases in immunocompromised adults have been reported.6,20 Although it has a clinical spectrum ranging from localized bullae to extensive exfoliation, with a frequently positive Nikolsky’s sign, its distinctive feature
includes the absence of painful experiences or mucosal involvement. The histological differentiation is
also simple: while TEN presents as a total necrosis
of the epidermal layer and its detachment from the
underlying dermis, SSSS is characterized by a partial
epidermal necrosis, with intraepidermal cleavage at
granular layer level without reaching keratinocytes39
- hence the absence of scarring sequelae.
Scarlatiniform rash, which is caused by group A
or
, can induce
widespread erythema, which is more marked at exion folds, with possible desquamation of the digital
pulps, pharyngitis, and a “strawberry-like” tongue.39
Another differential diagnosis to be considered is
the toxic shock syndrome caused by
, in which a diffuse erythema is accompanied
by desquamation (particularly of the palms and soles),
fever, and systemic involvement that develops rapidly into a shock situation.
Kawasaki disease (mucocutaneous lymph node
syndrome) is a multisystemic disease of unknown aetiology that affects children under ve years old and
results in fever, polymorphic skin rash, conjunctivitis, tongue ssures, and adenopathies, which is why
it is sometimes mistaken for TEN.18,39
Treatment
Considering that the onset of a systemic infection, which is favoured by skin denudation and
leukopenia, is the primary cause of death in TEN, the
rst step towards its management consists in promoting, as early as possible, the hospitalization of patients and their treatment in an intensive care unit
where such risks can be duly minimized and where
medical and surgical procedures can be undertaken
according to the clinical condition. Another issue to
be addressed, considering the fact that the patients
suffer heat loss through skin affected by epidermal
necrosis, resulting in discomfort, stress, and increased
metabolism, is the need to provide an environment
with the correct humidity level and a warm temperature, between 30 and 32 °C.18 A burns unit is the
setting that best offers these conditions - hence the
need to transfer patients as soon as possible,29,35,42-44 a
measure that by itself will reduce mortality.8,29,45
However, the treatment to be instituted should
take into account the existence of some major clinical differences compared to burn patients, namely the
involvement of the oropharyngeal mucosa (which interferes with adequate rehydration and nutrition), the
more diffuse character of skin lesions (impeding venous access), a stronger systemic expression,46 and a
reduced need for uid and protein-caloric intake.
On the patient’s admission to a burns unit, a detailed clinical history should be elicited, paying special
attention to all information regarding the possibility of
recent exposure to drugs or chemicals. It is also necessary to perform a thorough physical examination
and to determine the extent of the affected skin area
(using standard burn charts to assess burn extent).
It is crucial to discontinue non-essential medication,47
obviously including the drug suspected of having triggered TEN, making a decisive contribution to decreasing mortality.5 Blood samples should be collected as soon as possible in order to perform
haemograms, biochemical tests, and coagulation tests
on a daily basis, coupled with a regular collection of
specimens for bacteriological analysis44 (swabs of affected areas; sputum or tracheal aspirate; blood and
urine). As said, the diagnosis must be conrmed by
skin biopsy and histological examination. For the detection of pulmonary complications it is important to
perform regular oximetries and chest X-rays.42
After establishing the percentage of burn surface
area and the patient’s body weight, the total amount
of uid required for the replacement of water and
electrolytes lost through denuded areas can be determined according to one of the standard formulas
applied to burn patients (Parkland, Brooke, etc.); however, as already said, one should always bear in mind
that in TEN the amount of uid required is slightly
lower than that estimated for the management of
burns involving similar skin areas.48 Particularly during the acute phase, the uids should be supplied by
93
an intravenous route, and peripheral catheters should
be inserted in areas not affected by necroepidermolysis. In order to minimize the risk of infection, peripheral catheters should be preferred to central
catheters, which should be used only in the most serious cases and for as short a time as possible. The
urinary output will allow monitoring of the effectiveness of uid therapy, an acceptable minimum being
30-50 ml/h, as in thermal lesions. Vesicular tubes
should be removed as soon as the patient’s condition improves.
Patients should also be encouraged to use an oral
support for their rehydration and nutrition, although
the presence of oropharyngeal lesions may sometimes
determine the necessity of using a nasogastric feeding tube8 or even total parenteral nutrition, which increases the risk of infection.39 The risk of the development of stress ulcers determines the prescription
of antacids,8 although these may increase the risk of
bacterial colonization of the stomach - in such cases, the use of sucralfate may represent a benecial
alternative.
To prevent microbial colonization of denuded areas, it is fundamental to isolate the patient, adopt strict
aseptic techniques, perform hydrotherapy and apply
local antiseptic agents, remove crusts from oral and
nasal desquamation, and plan surgery carefully. If a
conservative surgical treatment is selected, hydrotherapy should be performed on a daily basis (or even
twice a day, according to some researchers), supplemented by the application of chlorhexidine48 or 0.5%
silver nitrate29,42 solutions over exfoliated areas dressed
with fat gauze. The use of silver sulphadiazine (Silvadene®, Flammazine®), silver sulphadiazine in association with cerium nitrate (Flammacerium®), and
mafenide acetate (Sulfamylon®) is contraindicated in
such patients, not only because they slow down the
re-epithelialization process but basically because
sulphonamides are the main causative agent of the
syndrome18,45 and tend to induce leukopenia.39
In terms of surgical treatment, there are two current schools of thought concerning the measures to
be adopted. One maintains that the patient should be
promptly taken to the operating room, preferably on
the very rst day, for debridement of patches of epidermal necrosis that are loose or easily detachable
(with a positive Nikolsky’s sign),6,20,30,39 followed by the
immediate coverage of exposed dermis with skin
xenografts,8,45,49 skin allografts,50 amniotic membrane,51
or synthetic skin substitutes,8,30,52 in order to prevent
its excision and microbial colonization,39 preclude systemic invasion, reduce uid and electrolyte loss, relieve pain, and promote re-epithelialization. The second current of thought adopts a more conservative
approach, maintaining that only epidermal patches that
are already loose and wrinkled should be removed,18
under intravenous sedation, and that the application
94
of biological or synthetic skin substitutes is not necessary for the patient’s survival or for effective re-epithelialization since the dermis is intact; it is thus sufcient to maintain asepsis of affected areas through
hydrotherapy and daily dressings with topical antibiotics until a new epidermal layer is formed.7,29,47 Supporters of this theory also point out the potential risk
from endotracheal intubation (which is necessary for
general anaesthesia in a broader surgical approach)
in a patient whose general condition is serious, with
easy detachable lesions in the oropharyngeal mucosae,
eventually leading to contamination of the bronchotracheal tree and the occurrence of pneumonia.7
The administration of corticosteroids in patients
with TEN, which was initially prescribed given the
fact that autoimmunity was considered one of the
main pathophysiological factors of this syndrome, has
been progressively ruled out since it was demonstrated that their immunosuppressive activity promoted the appearance of infectious complications and
masked the early signs of a possible septic picture,
thus postponing the beginning of treatment with all
the risks that this involved. Their use resulted in a
delay of the healing process and an increased risk of
gastrointestinal haemorrhage. Several researchers
have reported increased mortality in TEN patients
treated with these agents and advocate suspension
of any such therapy.8,19,29 Even those who still believe
that their use may have some advantages53,54 admit
that these are limited to administration in the early
stage of TEN, before desquamative lesions occur.45,46,54,55
The prophylactic use of systemic broad-spectrum antibiotics is discouraged in such patients,18,46
unless they present leukopenia.7 In the remaining cases, these agents should be administered on rst signs
and symptoms of septic complications (fever or hypothermia, oliguria, change in mental state, paralysed
ileum).46 As soon as the results of the bacteriological
analysis are obtained, it is mandatory to adjust antiinfectious therapy according to the results of antibiotic sensitivity tests. The presence of systemic fungal lesions (usually candidaemia) may require the administration of systemic anti-fungal drugs, and the
use of amphotericin B (liposomal) is generally indicated owing to its reduced toxicity and broad spectrum of activity.
The judicious use of analgesics (preferably opiates, because of the frequent association of TEN with
the administration of non-steroid anti-inammatory
drugs) and tranquillizers is indicated for most patients.
The risk of thrombo-embolic complications requires
the prophylactic administration of standard heparin18
or its derivatives of low molecular weight.39
The high rate of ocular complications suggests not
only the hourly administration of an ocular antiseptic
and/or antibiotic solutions to avoid the accumulation
of abrasive crusts over the cornea45 but also daily ob-
servation by an ophthalmologist, who will release any
synechiae that may have formed.18,20 Similarly, plaques
from oral and nasal desquamation should be carefully removed, prior to the application of a topical antiseptic.
Physiotherapy should be initiated on the rst day
of hospitalization in order to ascertain joint mobility,
since regular respiratory kinesiotherapy may effectively contribute to prevent the appearance of atelectasis and subsequent pneumonia.45
Plasmapheresis seems to be a promising therapeutic approach in the treatment of TEN.38,56 Although
it requires a venous access, this is a safe method
that provides quick pain relief and rapid cessation of
necrolysis, thus reducing the period of in-patient hospitalization.56 The removal of the offending drug and/or
its metabolites, as also of inammatory mediators, or
even of a potential “necrolytic factor”, provides the
rationale for its use in these patients.46
N-acetylcysteine, which is frequently used as a
mucolytic agent and also in the treatment of paracetamol intoxication, shows effective activity when used
in high doses in the treatment of patients with TEN.
Its activity is thought to be related to the support of
the anti-oxidant capability of cells, through the increase of intracellular levels of cysteine required for
the production of glutathione (serving as a buffer to
oxidant agents), and/or to the inhibition of the production of cytokines that mediate immunological reactions, such as the tumour necrosis factor · (TNF-·)
and interleukin-1 (IL-1), and of oxygen free radicals.57
Some researchers have proposed Pentoxifylline usually administered as a haemorrheologic agent to
reduce blood viscosity and improve ow conditions as another drug to be considered for the treatment
of TEN.58,59 In this particular case, its activity would
be to interfere with the binding of T-lymphocytes to
keratinocytes and also to inhibit the production of cytokines by macrophages and keratinocytes, including
TNF-·, IL-1, and IL-6.58
Given the similarity between TEN and the acute
phase of the graft-versus-host disease both in humans and in animal models,60 and also the immunological changes involved, especially the potential role
played by the mechanisms of cellular immunity in skin
necroepidermolysis, it is only reasonable to consider
the use of immunomodulators in its treatment. Several researchers advocate the use of cyclosporin60,61
because of its ability to inhibit the activity of T-lymphocytes and macrophages, the activity of cytokines
such as TNF-· and IL-2, and even the apoptosis of
keratinocytes, a mechanism that more than any other is responsible for the death of these cells;61 however, they underline the risk involved in the use of
an immunosuppressive drug in patients who are already immunocompromised60,61 and they therefore recommend the administration of low doses over during
short periods of time that have not been denitely
established.61 Following the same rationale, i.e. the
inhibition of cellular immunity and cytokine activity,
other researchers defend an alternative that consists
of the administration of cyclophosphamide,62 a cytotoxic agent commonly used in the treatment of neoplasia that has the same disadvantages as cyclosporin.
Some researchers recommend the use of granulocyte colony-stimulating factors to overcome neutropenia associated with TEN,63 thus reducing the risk
of sepsis.
In the literature, there is also a reference to the
treatment of such patients with a few sessions in a
hyperbaric oxygen chamber, in view of this technique’s
capacity to enhance epidermal regeneration and dermal
metabolism,
associated with an antiseptic activity and a potential
immunosuppressive effect;64 however, the effectiveness of this method has yet to be conrmed.
Prognosis
Numerous clinical and laboratory factors are related to poor prognosis in TEN patients. These include the involvement of extensive skin areas, delay
in withdrawing non-essential medication,5 old age, a
previously bad general condition, the intake of multiple drugs, the need for many blood transfusions,
and the prolonged re-epithelialization time of affected areas (more than 9 days). The results of laboratory tests show that persistent neutropenia is the
condition most commonly related to higher mortality, revealing reduced ability to resist infectious agents.
There is a very important logistic issue also associated with higher morbidity and mortality, namely delay (more than 48 h) in transferring patients to an
intensive care unit with adequate conditions for their
management, i.e. a burns unit.45,65
Treatment protocol for toxic epidermal
necrolysis
Extensive bibliographic analyses and discussion between members of the Clinical Staff at the Burns Unit
of Coimbra University Hospitals and colleagues from
other medical specialties permitted the adoption of a
protocol for the treatment of TEN that is currently
being applied and has yielded good results.
* Determination of the clinical history, focusing
on:
a) recent exposure to drugs, pesticides, and
“natural” products
b) factors associated with increased risk of TEN
(viral infections, lupus, haematological diseases, inammatory intestinal disease, graftversus-host disease, X-ray exposure, etc.)
c) factors determining bad prognosis (delay in
referral to a burns unit, involvement of an
95
extensive body surface area, persistent neutropenia, changes in renal function, old age,
poor nutritional status, intake of multiple
drugs, etc.)
* Assessment of affected area on admission, based
on standard burn charts used in burn patients
* Implementation of plan of action
a) withdrawal of all non-essential medication
and suspension of administration of corticosteroids
b) skin biopsy (to conrm clinical diagnosis)
c) intravenous uid therapy (based on formulas applied to burn patients and on the control of diuresis, which should be kept within a range of 30 to 50 ml/hr)
d) daily clinical analyses (complete haemogram,
complete biochemical test, coagulation test)
and regular (at least twice a week) culture
of specimens (skin exudates, blood, urine,
sputum or bronchial aspirate, tips of central
access catheters) for bacteriological analysis
and antibiotic sensitivity tests
e) chest X-rays and oximetries when the patient’s respiratory conditions are unclear (at
least twice a week)
f) prevention of stress ulcers with oral sucralfate
or, if not possible, intravenous ranitidine
g) analgesia with opiates
h) sedation with benzodiazepines
i) prophylaxis of deep vein thrombosis via subcutaneous administration of heparin with low
molecular weight
A
j) prescription of a high protein-caloric diet
k) prevention of ocular problems through daily
observation by an ophthalmologist, who will
prescribe appropriate ophthalmic medication
(articial tears, antiseptic solutions, topical
antibiotics) and release potential adhesions,
whenever necessary
l) joint and respiratory physiotherapy under the
supervision of a physiatrist
m)oxygen therapy through a cannula, or assisted ventilation according to the patient’s clinical condition and blood gas analysis
n) prevention of microbial colonization of denuded areas by means of:
1. strict aseptic techniques
2. daily hydrotherapy under intravenous sedation and with the application of a
chlorhexidine solution
3. removal of plaques from oral and nasal
desquamation
4. early surgery with removal of loose epidermal patches
5. coverage of denuded areas with skin allografts or synthetic skin substitutes
o) antibiotherapy, but only in the event of clinical and/or laboratory signs of infection (prophylactic use is contraindicated, except in patients presenting persistent neutropenia),
with broad-spectrum antibiotics; the corresponding dosage is adjusted in relation to
sensitivity tests
p) administration of inactivated human plasma
and intravenous perfusion of heparin (20,000
B
Fig. 1a, b, c - Case 1. Aspect of patient on admission to burns unit.
a. Involvement of ocular and oral mucosae.
b. Thorax involvement, with centripetal distribution of skin lesions.
c. Back involvement, showing epidermal sloughing and typical aspect of “wet clothes”.
96
C
U.I./day) in the event of a sudden increase of
FDP values
q) i.v. administration of high doses of N-acetylcysteine
r) therapeutic plasmapheresis - three sessions
on alternate days are usually enough
Clinical cases
We will now describe three clinical cases managed
in the burns unit of the Coimbra University Hospitals,
demonstrating the usual clinical course of such patients
and the application of the treatment protocol described.
NSGC, a 16-year-old black female, without any
signicant clinical history, was admitted to the burns
unit of the Coimbra University Hospitals presenting
eruptive-desquamative skin lesions spreading all over
the body except the feet and covering approximately 46% of its surface. The lesions in the upper and
lower limbs and the abdomen resembled small bullae with an erythematous outline, whereas the face
(
), thorax (
), dorsum (
), and anterior surface of the knees presented easily detachable plaques, with a positive Nikolsky’s sign. The patient’s oral and ocular mucosae were also affected:
she was feverish (peaks above 39 °C) and complained
insistently.
According to her clinical history, the patient had
been prescribed oral paracetamol ve days earlier,
following headache complaints. The following day she
had presented at the emergency service of a district
hospital because of the onset of the rst skin lesions, fever, and pruritus; she was then discharged,
after being advised to increase the frequency of the
administration of paracetamol to 1 g every two h.
The worsening of her clinical situation led to her hospitalization at Coimbra Hospital Center, where a diagnosis was made of TEN; she was transferred to
the burns unit of the Coimbra University Hospitals
on the following day. Considering the potential aetiological implications, it should be added that the
patient had a meal at a Chinese restaurant eight
days before her admission to the burns unit.
The patient received the routine in-patient hospitalization protocol of our burns unit and, apart from
the institution of intravenous uid therapy, was managed with enoxaparin (20 mg, s.c., in d.; sucralfate
(1 g, per os, 6 in d); N-acetylcysteine (200 mg, oral,
3 in d); morphine (5 mg, i.v., when necessary), plus
an oxytetracycline ointment applied in the eyes (3 in
d). On day 2 in the burns unit, the patient, under intravenous sedation, had a hydrotherapy session with
a chlorhexidine solution; she was then forwarded to
the operating room for removal of all devitalized, de-
tachable dermal tissue, with the application of a synthetic skin substitute (Omiderm®) in denuded areas.
The patient subsequently had several more hydrotherapy sessions (average, three sessions a week),
with further application of skin substitutes whenever
necessary.
On day 3 the patient continued to be febrile,
with leukopenia (4000/mm3) and increased FDP (3.1
Ìg/ml), which led to an update of the therapeutic
plan to high, intravenous doses of N-acetylcysteine
(2 g, 4 in d) and the initiation of antibiotherapy with
ceftazidime (1 g, i.v., 3 in d). The presence of
coughing and moderate dyspnoea, as well as an
oximetry with a pO2 of 56%, supported the institution of oxygen therapy through a nasal cannula with
a ow rate of 8 l per min. The rst plasmapheresis
session was performed on the same day. On day 4
there was a clinical improvement and the patient
Fig. 2a - Case 1. Follow-up at 18 months.
Facial hypopigmentation and loss of cilia.
was given inactivated fresh plasma. The plasmapheresis session was repeated on day 5. On day 6
Fig. 2b - Case 1. Follow-up at 18 months.
Large hypochromic spots in the thorax and upper limbs.
97
the patient’s oximetry already showed a pO2 of 100%,
although the presence of anaemia (with a haemoglobin level of 9 g/dl) and an FDP value of 3.3 Ìg/ml
led to the administration of two erythrocyte units
and three units of inactivated fresh plasma. On day
Fig. 2c - Case 1. Follow-up at 18 months.
Hypertrophic scarring and hypopigmentation in the back.
vest. The patient was also advised to perform skin
hydration with a fat cream and to use sunscreen.
The patient’s eyes presented slight photophobia
and epiphora, as well as a rarefaction of the palpebral cilia without any changes in visual acuity. The
patient has since been regularly followed at the ophthalmology department of Coimbra University Hospitals.
FGC, a 64-year-old Caucasian male with chronic
renal failure, dyslipidaemia, and arterial hypertension
(usually managed with irbesartan), was admitted to
the burns unit of the Coimbra University Hospitals.
The patient presented eruptive-desquamative skin lesions, with a positive Nikolsky’s sign covering approximately 45% of the body surface, conuent in
large plaques on the face (
), thorax (
),
abdomen, upper dorsum, and soles, and resembling
small bullae scattered over remaining body areas. As
in the previous case, the oral and ocular mucosae
were affected and the patient was subfebrile.
Two days before the onset of high fever (39 °C),
the patient’s clinical history reported purulent conjunctivitis, odynophagia, vesicular lesions in the oral
mucosa, and bullae scattered all over the body, which
determined his consultation with a general practitioner
and the prescription of an oral, long-acting association of amoxicillin with clavulanic acid - oral nimesulide plus chloramphenicol, both as a collyrium and
as an ophthalmic ointment. Since there was no improvement, the patient presented to the local health
7 improvement of the respiratory condition made it
possible to reduce the administration of oxygen to
4 l/min (with nal denite suspension on day 22).
On day 8 the patient had her nal plasmapheresis
session, by which time she was already subfebrile,
with 8,400 leukocytes/mm3, an FDP value of 1.7
Ìg/ml, and a haemoglobin level of 11.8 g/dl.
The patient’s condition continued to improve
favourably and the administration of ceftazidime and N-acetylcysteine was suspended on day 12. Cutaneous tissue (and
the oral mucosa) showed a sustained
and relatively quick re-epithelialization,
which allowed the patient to be discharged home after 26 days of hospitalization.
During the whole hospitalization period, the patient was followed daily by
an ophthalmologist, who performed the
debridement of the conjunctival cul-desac when necessary.
During regular follow-up visits at the
out-patient department of the burns unit,
the lesions showed a good evolution, although there were some sequelae. The
patient presented slight cutaneous
hypochromia in the face (
) and
marked hypochromic maculae on the affected areas of the anterior trunk (
Fig. 3a - Case 2. Aspect of patient
, dorsum, and limbs. The existence of
on admission to burns unit.
small hypertrophic scarring areas on the
Ocular and facial involvement.
dorsum (
) conditioned the institution of pressotherapy with a pressure
98
Fig. 3b - Case 2. Aspect of patient
on admission to burns unit.
Thorax involvement showing target
lesions.
care centre the following day and was instructed to
suspend the medication that had initially been prescribed and to replace it with clarithromycin, as an
oral suspension, oral oxatomide, and oxytetracycline
as an ophthalmic ointment. The following morning he
was observed by a private doctor owing to the worsening of his lesions, and he was prescribed a combination of ammonia liquor, pentamethylenetetrazol,
sodium benzoate, sulphadiazine, and balsamic syrup
as an oral suspension, oral promelase, oral doxycycline, and oral rifampicin. Finally, he presented at the
emergency room of a general hospital later in the
with intravenous uid therapy: ranitidine (50 mg, i.v.,
3 in d); enoxaparin (20 mg, s.c., in d) and chloramphenicol (ophthalmic ointment, 3 in d). On day
2 ranitidine was replaced with sucralfate (1 g, oral,
6 in d) and the chloramphenicol ointment was replaced with oxytetracycline ointment plus N-acetylcysteine (2 g, i.v., 4 in d). On day 3 the patient received hydrotherapy, after which he started presenting fever peaks above 38.5 °C and a high FDP
value (18.5 Ìg/ml), necessitating the administration
of inactivated fresh plasma and intravenous perfusion of heparin (20,000 U.I./day) instead of enoxaparin, a regimen that was maintained until 18 February 2002. On day 4 he was taken to the operating room for removal of all detached epidermal tissue. In the post-operative period, the patient had
high fever peaks (above 39 °C), and the occurrence
of moderate dyspnoea led to the institution of oxygen through a nasal cannula (4 l/min). On the same
day the patient underwent his rst plasmapheresis
Fig. 4a - Case 2. Patient at end of rst week in burns unit.
Ocular and facial involvement.
evening, where he was immediately forwarded to the
Coimbra University Hospitals with a diagnosis of
Fig. 5a - Case 2. Follow-up
at two months.
Ocular and facial aspect.
Fig. 4b - Case 2. Patient at end of rst week in burns unit.
Thorax involvement and application of epidermal substitutes.
Stevens-Johnson syndrome/TEN. No relation was
found between the onset of TEN symptoms and a
probable intake by the patient of suspect drugs.
After the patient’s admission to our burns unit,
the home medication was suspended and replaced
Fig. 5b - Case 2. Follow-up
at two months.
Thorax aspect, showing hypertrophic
scarring and
hypochromia.
session. On day 5 oxygen therapy was suspended;
the patient remained subfebrile, the FDP value
reached 2.2 Ìg/ml, and a second plasmapheresis session was performed. On day 6 the patient presented a favourable improvement in his skin lesions (
) and we applied a synthetic skin substitute (Omiderm®) to his thorax (
) and dorsum; he also
had a third and nal plasmapheresis session. On day
12 the high febrile peaks recurred, requiring the institution of empirical intravenous antibiotherapy with
ceftazidime, replaced by teicoplanin on day 17, following the outcome of the bacteriological analyses
and sensitivity tests, which showed the presence of
susceptible only to teicoplanin
and vancomycin. On the same day, the observation
99
of an FDP value of 23.6 mg/ml led to a further administration of inactivated fresh plasma and an intravenous perfusion of heparin, which proceeded until day 23. On day 21 there was a complete re-ep-
Fig. 6a - Case 3. Thoracic lesions.
Aspect during hospitalization in burns unit, showing bullae conuence and sloughing of skin.
ithelialization of all body surface areas and the patient was subfebrile. On day 23 his clinical condition
was good - he was apyretic, presented a normal FDP
value, and all medication was suspended. He was
discharged on day 24.
As in the previous case, the patient was closely
followed by an ophthalmologist, who performed the
lysis of ocular adhesions when necessary.
During follow-up visits at our burns unit out-patient department, a number of skin and ocular sequelae (
) were observed. He now presents
marked erythema on the thorax (
) and melanic, dyschromic maculae on the remaining affected areas; his facial erythema is milder, without any
dyschromic areas. The patient also presents irregularities in the matrices and nail beds of the hands
and feet. He has been advised to perform skin hydration with a fat cream and to use sunscreen.
The patient has been regularly followed at the
ophthalmology department of the Coimbra University
Hospitals; he suffers from photophobia and xerophthalmia (for which he has been prescribed collyrium
and articial tears), rarefaction of the palpebral cilia
and also symblepharon in the lower right eyelid.
VAC, a 15-year-old Caucasian male, was admitted to our burns unit presenting eruptive-desquamative skin lesions (
) spreading all over the body,
with a mixture of fully developed blisters and target
lesions covering approximately 70% of its surface. His
body temperature was over 39º C; Nikolsky’s sign
100
was positive and the ocular and oral mucosae were
involved, and a diagnosis of TEN was pronounced.
With a previous history of allergic rhinitis, the patient had started with a sore throat eight days before admission, for which he was given 1 g of oral
paracetamol. The following day he had high fever and
myalgia, and the family doctor prescribed oral
azithromycin. A few hours after the rst administration he developed a cutaneous rash, and two days
later he was given oral ibuprofen, prednisolone (oral
and i.v.), and an oral anti-histaminic (oxatomide). The
same night he noticed the appearance of blisters on
the trunk and he was admitted to a regional hospital, where he stayed until being transferred to the
burns unit of the Coimbra University Hospitals owing
to the deterioration of his clinical status.
During his hospitalization in the burns unit, the
patient was put on standard uid therapy. He received enoxaparin (20 mg, s.c., in d), sucralfate (1
g, oral, 6 in d), N-acetylcysteine (2 g, i.v., 4 in d),
Fig. 6b - Case 3. Thoracic lesions.
Follow-up at three months.
ceftazidime (1 g, i.v., 2 in d), morphine, i.v. perfusion of 2 mg/h, and inactivated fresh plasma (average of 3 units per day from day 5 to day 14), as
well as cycloplegicedol solution and oxytetracycline
ointment applied on the eyes (monitored daily by an
ophthalmologist). On day 2 all devitalized, detachable
dermal tissue was removed, and the patient received
daily hydrotherapy until the end of his stay. Also on
day 2 he underwent a rst session of plasmapheresis, and a second session on day 4. When mild anaemia
developed (9.0 g/dl) on day 7), the patient was given two units of whole blood. Microbiological cultures
from skin and body uids were consistently negative.
After day 9, the patient’s temperature dropped to
below 38.5 ºC, and he became apyretic on day 11;
the value of the leukocytes varied from a maximum
of 15900/mm3 on day 3 to a minimum of 5300/mm3
on day 13. The FDP value fell from a peak of 5.2
Ìg/ml to a minimum of 2.4 Ìg/ml on day 13.
The re-epithelialization of the denuded areas was
very quick and the patient was discharged on day 16.
He has been followed up at the burns unit outpatient department. Three months post-discharge his
face has a normal appearance, without any ocular sequelae, while there are some zones of mild cutaneous
hypochromia on the anterior trunk (
), dorsum,
and limbs. The patient has no functional limitations,
and has been advised to perform skin hydration with
a fat cream and to use sunscreen.
Conclusion
The high mortality and morbidity associated with
TEN make it necessary to familiarize all physicians
with this syndrome, in particular those practising in
health care centres and county and district hospitals,
given the high risk arising from late diagnosis and
therapy. In all cases presenting with erythematous or
bullous eruptions associated with drug intake, this differential diagnosis should be excluded systematically
and at an early point in time. Prompt referral to hospitals possessing a burns unit should be routine practice in suspect cases. The early suspension of all nonessential medication is crucial and this may alter the
prognosis. The patients should be regarded as burn
patients, and the new treatment procedures described
here present promising signs and should be carefully considered and implemented, whenever possible,
in patients with TEN. The existence in specialized units
of a treatment protocol, which is certainly incomplete
and constantly being updated, ensures a minimum
standard that is fundamental to enable patients to receive adequate care and, simultaneously, to allow
comparison of the results obtained.
RÉSUMÉ. La nécrolyse épidermique toxique (NET), ou syndrome de Lyell, est une lésion dermatologique rare mais
très grave, caractérisée par le brusque commencement d’une èvre élevée, par des signes de toxicité systémique et
par une intense exfoliation mucocutanée. La pathophysiologie n’est pas encore bien déterminée, bien que la présence
d’une base immunologique soit unanimement reconnue. La NET se manifeste après l’administration d’un médicament
et, malgré qu’elle soit autolimitée en absence de complications, elle s’associe, si non bien contrôlée, à une morbidité
et une mortalité élevée due dans la plupart des cas au développement du sepsis. Le traitement principal est la suspension immédiate du médicament coupable et l’hospitalisation précoce du patient dans un service qui peut offrir des
soins intensifs et minimiser le risque de l’infection et qui en outre offre les conditions pour la réalisation du débridement chirurgical et la couverture de zones touchées, c’est-à-dire une unité des brûlures. On continue à étudier diverses
mesures thérapeutiques pour diminuer la morbidité et la mortalité de ce syndrome, y inclus l’emploi de la plasmaphérèse, l’administration de doses élevées de N-acetylcysteine, l’immunosuppression et l’oxygène hyperbarique. Les Auteurs présentent le protocole de traitement suivi à l’Unité des Brûlures de Coimbra (Portugal) et l’illustrent avec trois
cas cliniques qu’ils ont traités.
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This paper was received on 2 December 2003.
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