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com

Review

A review of causes of Stevens–Johnson syndrome

and toxic epidermal necrolysis in children
Carla Ferrandiz-Pulido, Vicente Garcia-Patos

Facultat de Medicina, ABSTRACT number of patients, which complicates the possibil-

Department of Dermatology, Stevens–Johnson syndrome (SJS) and toxic epidermal ity of drawing real conclusions.
Hospital Universitari Vall
d’Hebron, Universitat
necrolysis (TEN) are rare life-threatening conditions SJS/TEN has been observed worldwide with an
Autònoma de Barcelona, almost exclusively attributed to drugs. The incidence annual incidence of 1–2 cases per million inhabi-
Barcelona, Spain in children is lower than in adults and has a better tants,5 and occurs in all age groups including chil-
outcome. Mycosplama pneumoniae infection may be dren, infants and even newborns, who comprise
Correspondence to
involved in some cases of paediatric SJS. The main 10–20% of reported paediatric cases.6 The inci-
Dr Carla Ferrándiz-Pulido,
Department of Dermatology, etiologic factors for both SSJ and TEN are sulphonamides dence increases with age likely due to increases in
Hospital Universitari Vall and anticonvulsants, followed by penicillins and non- drug prescriptions and comorbidities modifying
d’Hebron, Passeig Vall steroidal anti-inflammatory drugs. In rare instances, drug effects. Adult SJS may lead to death in up to
d’Hebron 119-129, paracetamol is the only suspected drug. By contrast with 5%, while 30% of cases of adult TEN may be
Barcelona 08035, Spain;
[email protected] adults, allopurinol, oxicams and nevirapine are not fatal.5 Mortality rates in children are highly vari-
identified as causative agents in children, probably due able, but seem to be lower than in adults.6 7
Received 26 March 2013 to differences in drug prescriptions. The only aspects of Sequelae of SJS/TEN are most commonly related to
Revised 18 June 2013 treatment that have been proved to improve survival are mucosal involvement, mostly ocular.8
Accepted 25 June 2013
Published Online First
the rapid withdrawal of the suspected offending drugs
19 July 2013 and an optimal supportive therapy with emphasis in
nutritional support, accompanied by management of CLINICAL MANIFESTATIONS
denuded skin areas. The use of specific therapies Clinical manifestations in children overlap with
remains controversial. clinical presentation in adults.9 SJS/TEN is an acute
inflammatory disease, characterised by fever,
Drug therapy

malaise, cutaneous and mucosal lesions, commonly

INTRODUCTION preceded by prodromal symptoms lasting 1–7 days.
In 1922, Stevens and Johnson described two chil- The prodromal period is characterised by non-
dren who developed an acute mucocutaneous syn- specific symptoms, such as malaise, fever, ocular
drome characterised by extensive mucosal necrosis pruritus and dysphagia. Erythema, erosions, scabs
and purpuric macules on the skin associated with and pseudomembranes gradually develop in the
fever, stomatitis and ophthalmia, with a probable oral, genital and ocular mucous membranes.
infectious origin.1 Thereafter in 1956, Lyell Inflammation and soreness of the mouth and geni-
described four patients who developed a more talia is frequent, and usually precedes the skin
extensive skin necrosis, resembling scalding of the lesions by a few days3 7 10 (figure 1).
skin.2 These conditions became widely known as Skin lesions vary in severity, presenting as red
Stevens–Johnson syndrome (SJS) and Lyell syn- macules and papules that sometimes coalesce to a
drome or toxic epidermal necrolysis (TEN), generalised erythematous rash with atypical targe-
respectively. SJS and TEN are rare, life-threatening, toid lesions, and progress to vesicles, bullae and
severe cutaneous adverse reactions that affect both extended skin necrosis that detaches in large
adults and children. The considerable overlap in sheets9 10 (figures 2–4). When the leading cutane-
the cardinal clinical, aetiological and histopatho- ous finding is erythema, the Nikolsky sign may
logical features of both entities justifies them to be guide the diagnosis, although it is not exclusive of
considered clinical presentations of the wider spec- SJS/TEN. Nikolsky sign is defined as an epidermal
trum known as ‘SJS/TEN’.3 4 The main difference detachment that appears when applying a tangen-
lies in the percentage of body surface area (BSA) tial pressure on erythematous, non-blistering skin.
presenting skin detachment, and is defined SJS In cases with a Nikolsky sign, the patient should be
when epidermal detachment affects less than 10% admitted to a burn care unit with a suspect diagno-
of BSA, SJS/TEN overlap when the detachment sis of SJS/TEN.3
ranges from 10% to 30%, and TEN when it affects Practically all patients present affected mucous
more than 30%.3 Herein, we make an update on membranes with varying severity, which is often
SJS/TEN in children, focusing on clinical manifesta- painful and haemorrhagic. Common symptoms
tions and clues to differential diagnosis, pathogen- include purulent conjunctivitis and inflammation,
esis, identification of medications associated with a erosions, ulcers and crusts of other mucosal sur-
risk for SJS/TEN, diagnosis and management. faces like the mouth, nose, pharynx, respiratory
Childhood SJS/TEN presents several unique and digestive tracts, and anogenital mucosa, which
aetiological, prognostic and therapeutic challenges, may result in potentially life-threatening complica-
To cite: Ferrandiz-Pulido C, and despite there being an extensive work of litera- tions, such as bleeding and infection.8 Very severe
Garcia-Patos V. Arch Dis ture regarding this topic in paediatric patients, most cases may additionally develop renal and/or hepatic
Child 2013;98:998–1003. publications refer to single case reports or a small failure.

998 Ferrandiz-Pulido C, et al. Arch Dis Child 2013;98:998–1003. doi:10.1136/archdischild-2013-303718

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Figure 1 A 17-year-old male patient diagnosed with Stevens-Johnson Figure 3 Initial phase of toxic epidermal necrolysis with diffuse
syndrome due to azitromicine. Erosions and crusts on the lips with erythema and vesicles that will evolve to full epidermal necrosis.
diffuse ulcers on the tongue.

of typical target lesions showing three concentric well-defined

DIFFERENTIAL DIAGNOSIS areas of different skin colour or raised atypical targetoid lesions
SJS/TEN represents a very severe form of drug-induced reaction. at acral sites. There often appears a subtle inflammation of the
The differential diagnosis includes entities such as drug-induced oral mucosa accompanied by a swollen lip, but not a true mucosi-
linear IgA. Linear IgA is an autoimmune subepidermal blistering tis with erosions and haemorrhagic crusts like in SJS/TEN. It
disease that may be associated with drug exposure (mainly, affects predominantly young and healthy people, and herpes
vancomycin). The diagnostic hallmark of this condition is the simplex virus may be responsible for most cases. The clinical
linear deposition of IgA at the basal membrane of perilesional course is mild and may frequently recur. It is considered a distinct
skin observed by direct immunofluorescence.11 Other entities entity from SJS/TEN.15 16
that should be ruled out include drug rash with eosinophilia and
systemic symptoms (DRESS), a multisystemic disorder charac- PATHOGENESIS

Drug therapy
terised by a skin eruption with oedema that evolves to form blis- SJS/TEN is considered a delayed-type hypersensitivity reaction
ters, accompanied by peripheral eosinophilia >1.5×109/L, (or type IV reaction), reinforced by the fact that these reactions
atypical lymphocytes and systemic abnormalities.12 Most resolve upon removal of the drug and occur more rapidly on
common drugs responsible for this disease are anticonvulsants, drug reintroduction.17 18
However, the immune-
sulphonamides, minocycline and allopurinol. A drug-induced physiopathology of SJS/TEN is not fully understood and
maculo-papular exanthema should also be excluded, as this is the remains controversial. The major pathological finding in this
most common cutaneous adverse drug reaction. This rash may disease is a widespread apoptosis of keratinocytes, but it is still
evolve to an extensive desquamation which can occasionally be unknown how a certain drug may actually induce epidermal
confused with TEN. Mucosal involvement is rare. Sometimes, at necrosis. The Fas-Fas ligand interaction and activation of
the onset of the rash, a more ‘dusky’ hue of the lesions may caspase enzymes are pathways involved in apoptosis that could,
support a diagnosis of SJS/TEN, as it is thought the darker hue in part, be responsible for this disease. On the other hand, TEN
may herald the skin detachment.13 Staphylococcal scalded skin and SJS blisters have shown to be rich in cytotoxic T-cells and
syndrome (SSSS) should also be included in the differential diag- natural killer cells that would induce damage via perforin/gran-
nosis. The syndrome is induced by epidermolytic exotoxins A zyme B/granulysin and tumour necrosis factor-α.6 19
and B, which are released by Staphylococcus aureus. The clues Over the last decade, there have been many associations
for correctly identifying SSSS include the absence of mucosal between SJS/TEN and Class I and II Human Leucocyte Antigens
involvement, a Nikolsky sign present in both erythematous and
‘apparently normal’ skin and no prior history of drug intake.14
Finally, erythema multiforme is characterised by the appearance

Figure 2 Atypical target lesions in a 1-year-old female patient with Figure 4 A 5-year-old female patient with toxic epidermal necrolysis
Stevens–Johnson syndrome due to phenobarbital. with three suspected drugs ( penicillin, ibuprophene and paracetamol).

Ferrandiz-Pulido C, et al. Arch Dis Child 2013;98:998–1003. doi:10.1136/archdischild-2013-303718 999

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(HLA) alleles of the MHC (major histocompatibility complex). M pneumoniae and SJS/TEN has been established in cases of
Several non-mutually exclusive models have been proposed to documented SJS without prior exposure to any drug. An inter-
explain how small molecular synthetic compounds (the drugs) esting study of Kunimi et al compared the clinical characteristics
are recognised by T cells in an MHC-dependent fashion, includ- between drug-induced SJS and M pneumoniae-associated SJS in
ing the hapten concept/prohapten model, the p-i model an Asian population. They found no differences with regard to
( pharmacological interaction of drugs with immune receptors), skin, oral or genital lesions, but ocular involvement was signifi-
and the altered repertoire model.18 cantly more frequent in M pneumoniae-associated SJS than in
Genetic susceptibility also plays a crucial role in the develop- the drug-induced group (94% vs 64%). With regard to internal
ment of SJS/TEN. HLA-B1502 has been associated with organ involvement, hepatitis was more frequent in drug-induced
carbamazepine-induced SJS in a Han Chinese population,20 and SJS, while respiratory disorders predominated in the M
HLA-B5801 with allopurinol-induced SJS/TEN has been linked pneumoniae-associated SJS.25
to a Japanese population.21 However, those findings could not More than 200 drugs have been associated with SJS or TEN,
be confirmed in Europe. Thus, the risk of SJS/TEN is related to most commonly sulphonamides, anticonvulsants, non-steroidal
the exposure with high-risk drugs, and also to a genetic predis- anti-inflammatory drugs (NSAID) (oxicams), allopurinol and
position.22 In order to improve the safety of drugs, it would be penicillins.24 27 28 Most studies in children describing aetio-
interesting to evaluate on preclinical drug screening programmes logical factors are single case reports, although there are a few
the interaction between the drug and the HLA.17 series reported (table 1).9 24 26 27 29–31
On the other hand, drug reactions generally occur with The largest cohort was published by Levi et al and used a
greater frequency in situations where there is a build up of pooled analysis from two multicentre case-control studies
chemically reactive metabolites, for example, when a decrease in (SCAR – severe cutaneous adverse reactions – and euroSCAR)
enzymatic metabolism is found. In this sense, polymorphisms in including 80 patients and 216 matched controls below the age
gene families of detoxifying enzymes have been identified, of 15, and concluded that sulphonamides and anticonvulsants
above all in the CYP450 family, which affect drug kinetics and (phenobarbital, lamotrigine, and carbamazepine) were the most
toxicity. Moreover, some patients with SJS/TEN have a low frequent causative drugs.24 Recent infection with M pneumoniae
N-acetylating capacity, which predisposes them to serious cuta- had been reported in 9% of cases in this cohort, and the
neous adverse reactions.23 window of drug exposure was restricted to 7 days prior to the
index day, except for phenobarbital, which has a longer half-life,
AETIOLOGY where it was extended to 3 weeks.
Most cases of SJS/TEN are clearly linked to medications; however, To summarise, most studies in children conclude that the
Drug therapy

in approximately 5% of cases a drug cannot be identified.24 highly suspected drugs responsible for SJS/TEN are sulphona-
Although TEN is almost exclusively attributed to drugs, some mides and anticonvulsants, including phenobarbital, lamotrigine
cases of SJS may be caused by Mycoplasma pneumoniae infec- and carbamazepine.9 26–31 However, other drugs, such as peni-
tion.25 Infections by virus (coxsakie, influenza, Epstein–Barr, cillins, cephalosporins (a drug rarely involved in adult SJS/
human herpes virus 6 and 7, cytomegalovirus, parvovirus), bac- TEN), valproic acid, NSAIDs (excluding oxicams in this age
teriae (streptococcus β-haemolyticum, group A), mycobacterium, group), and paracetamol may pose a potential risk in chil-
and rickettsia could be potential cofactors or triggers in associ- dren.24 26 27 31 By contrast with adults, allopurinol, nevirapine
ation with drugs.6 By contrast with adults, the number of and oxicam NSAIDs were not identified as causative agents in
published cases in the literature reporting comorbidities is low, children.28 Drug prescription patterns may be responsible for
with a single case of SJS/TEN arising in a patient with Crohn’s, the changes in the drugs held responsible for disease. In chil-
and no patients with HIV, lupus erythematosus, or cancer having dren, anticonvulsants might be mainly used for seizures and
been published.23 26 As only two paediatric case series with a attention deficit and hyperactivity disorder. Valproic acid has
complete prior history are reported, it is impossible to conclude been identified as an independent risk factor from other highly
whether the aforementioned disorders pose a potential risk for suspected antiepileptic agents evaluated, and it seems to also
SJS/TEN development in children as they do in adults. convey a higher risk for SJS/TEN.24 Among antibiotics, sulpho-
SJS/TEN is considered to be drug related if the patient is namides have become a second-line treatment in most infec-
exposed to the offending agent within 8 weeks prior to the tions, but are also used for chronic digestive diseases, such as
onset of the rash. An infectious origin is considered if the infec- Croh ns or ulcerative colitis. Other antibiotics include penicillins,
tious process is noted to take place 1 week prior to the onset of cephalosporins and macrolides, all of them linked to SJS/TEN
the rash, and titre and/or cold agglutinins (IgM) of the infec- in several studies of single patients.26 27 30 31
tious agent are available.26 27 Sometimes, both drugs and infec- Importantly, in most cases of children with SJS/TEN, there is
tious agents are identified as possible precipitants to the disease, more than a single drug that could be considered suspect and,
which makes identifying the real culprit a difficult task. For therefore, the term ‘suspicious’ rather than ‘causative’ should be
example, when the beginning of the suspicious drug intake used.24 26
concurs with the prodromal symptoms of the rash, the drug
could represent treatment of the underlying illness and not a DIAGNOSIS
causal association with SJS/TEN. It is biologically plausible that The diagnosis of SJS/TEN is mainly clinical, although a skin
an interaction between an infectious agent and a drug or its biopsy showing full epidermal thickness necrosis accompanied
metabolite, may precipitate severe skin reactions.27 The infec- by a scarce dermal inflammatory infiltrate may help confirm the
tion would probably act as a cofactor in those cases. diagnosis.
Mycoplasma pneumoniae mainly causes atypical pneumonia, Pinpointing the exact causative agent may be difficult, as
but it can also lead to neurological, hepatic and cardiac disor- there is no definitive laboratory test to confirm the role of
ders. Moreover, it has been demonstrated to cause SJS predom- suspect agents. In children, disease is more likely to be linked to
inantly in childhood and adolescence, a period where infections a drug as they are usually treated with a lower number of drugs.
by this agent are more frequent.25 A clear relationship between When we suspect a diagnosis of SJS/TEN, we must obtain a

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Table 1 Review of literature of causes of SJS/TEN including all case series with 10 or more paediatric patients
First author Number of paediatric
(year of publication) patients Aetiology Main drugs involved

Spies et al (2001)29
15 TEN ▸ 100% drugs Antibiotics (sulphonamide, penicillin, cephalosporin,
tetraciclin) and anticonvulsants (phenobarbital, phenitoin)
Forman et al (2002)27 61 (EM, SJS, TEN) ▸ TEN: 100% drugs Sulphonamides and penicillins, followed by cephalosporins
▸ SJS: 61% drugs, 25% infection, 14%
both
Sheridan et al (2002)30 11 SJS/TEN ▸ 82% drugs Anticonvulsants, antibiotics and NSAID
▸ 18% infection
Lam et al (2004)9 11 SJS/TEN ▸ TEN: 100% drugs Anticonvulsants (carbamacepine, lamotrigine, valproat sodium)
▸ SJS: 75% drugs, 25% infection
(M. pneumoniae, VHS)
Levi et al (2009)24 80 SJS/TEN ▸ 91% drugs Antibiotics (sulphonamide, penicillin, cephalosporin and
▸ 9% Mycosplama pneumoniae macrolide) and anticonvulsants (phenobarbital, lamotrigine,
and carbamazepine). Others: valproic acid, NSAIS and
paracetamol
Koh et al (2010)31 15 SJS/TEN ▸ 74% drugs Anticonvulsants (carbamazepine, valproate, and lamotrigine)
▸ 20% M pneumoniae and betalactams
Ferradiz et al (2011)26 14 SJS/TEN ▸ 93% drugs Anticonvulsants (carbamazepine, lamotrigine, phenobarbital)
▸ 7% drug and M pneumoniae and antibiotics (penicillin, cephalosporin and macrolid).
Others: sulphonamide, NSAID
EM, erythema multiforme; NSAID, nonsteroidal anti-inflammatory drugs; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

detailed medical history listing all new medications taken during 30% factor to resting energy requirements should be made
the 8 weeks prior to the disease onset, although in our experi- when calculating nutritional support.38
ence, the most important window is the 1 or 2 weeks prior to The local wound treatment is important to avoid complications
the onset of the eruption. derived from the loss of barrier function, and includes gentle

Drug therapy
Moreover, an infectious origin should always be ruled out and debridement of broken blisters, removal of necrotic epithelium,
patients should be tested with serology tests (IgM and IgG) and topical treatment with antimicrobials, and wound coverage with
PCR (to assess viral replication) for herpes simplex virus 1 and 2, either biological or traumatic biosynthetic wound dressings.37 In
varicella-zoster virus, cytomegalovirus, Epstein–Barr virus, our opinion, silver sulfadiazine-impregnated dressings should be
human herpes virus 6 and 7, parvovirus and M pneumoniae.25 32 used, except when sulphonamides are included in the suspected
There is some controversy regarding the usefulness of drugs, as these dressings are safe, effective and inexpensive.
lymphocyte transformation tests to find causative drugs, with Literature of specific treatment in children is scant and con-
results showing many false positive and negative results. This is troversial, with a lack of clinical trials, and only a few observa-
a safe and reproducible test used to assess activation of drug- tional studies hindered by a low number of patients. In general,
specific T cells in vitro, but in SJS/TEN, it needs to be per- there are two principal trends toward specific treatments for
formed within the first week after onset of the rash to aid in the SJS/TEN in children. The most commonly studied therapy by
diagnosis.33 Patch testing has not proven useful in SJS and TEN. far is the use of intravenous immunoglobulins (IVIG), followed
Drug challenges with suspected drugs are contraindicated in by corticosteroid treatment. IVIG have shown promising results
TEN, because second episodes can be fatal. because it inhibits Fas-mediated apoptosis in sensitive cell lines
by blocking Fas receptors. Most studies have shown that, when
used at a dose of 2–4 g/kg within the first 4 days of onset of
TREATMENT skin eruptions, patients appear to have a shorter time to cessa-
The most important actions to be taken when a child is affected tion of disease progression and complete re-epithelisation, and
from SJS or TEN are the rapid withdrawal of the offending also have trend towards a better survival rate.39–41 On the con-
drug and a prompt admission to a specialised burn unit or trary, a few studies did not show any benefit on mortality
paediatric intensive care unit, as this has been shown to directly rates.42 On the other hand, corticosteroids have shown good
decrease morbidity and mortality rates.29 33–37 It is therefore results in some studies, mostly when used during the first days,
crucial to increase awareness of SJS/TEN and aim for early spe- but also an increased risk of complications and a failing of effi-
cialist referral. cacy in some cases.19 43
General care measures include the care by multidisciplinary Other specific treatments include cyclosporine, plasmapher-
teams which include specialist physicians and nurses versed in esis, TNF-α inhibitors or a combination of different drugs.19 43
managing extensive cutaneous denouement and mucosal slough- In adults, the only therapeutic measure which has proven effect-
ing. Full care of the patient includes ophtalmological revisions ive at reducing mortality rates is intensive supportive care.44 On
and supportive care, with special emphasis on wound manage- the contrary, a recently published meta-analysis focused on man-
ment, fluid balance, respiratory and nutritional support, aggres- agement of SJS/TEN in children, found that patients treated
sive septic monitoring, pain management, physical and only with care support had a higher morbidity and mortality,
occupational therapy and psychosocial attention.29 34–37 The and although the literature is scant, patients treated with steroids
nutritional needs of children with SJS/TEN is an aspect of care and IVIG seemed to have a better outcome.43
that is often neglected. Energy requirements of paediatric Systemic antibiotics should only be considered in patients
patients with SJS/TEN are increased, and the application of a with clinical signs of infection, and always guided by sensitivity

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assays from systematic cultures of the skin, mucosae, catheters 13 Lin TK, Hsu MM, Lee JY. Clinical resemblance of widespread bullous fixed drug
and urine.45 eruption to Stevens-Johnson syndrome ortoxic epidermal necrolysis: report of two
cases. J Formos Med Assoc 2002;101:572–6.
SCORTEN is a TEN-specific severity of illness score used to 14 Macias ES, Pereira FA, Rietkerk W, et al. Superantigens in dermatology. J Am Acad
predict the risk of complications and mortality and is calculated Dermatol 2011;64:455–72.
within 24 h after admission. It is also used to evaluate if a thera- 15 Assier H, Bastujigarin S, Revuz J, et al. Erythema multiforme with
peutic intervention reduces the complications that we observe mucous-membrane involvement and Stevens-Johnson Syndrome are clinically
different disorders with distinct causes. Arch Dermatol 1995;131:539–43.
versus what was expected based on the SCORTEN predic-
16 Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical
tion.46 47 It is based on seven prognostic factors: age, malig- patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and
nancy, surface area involved, heart rate, serum urea, bicarbonate toxic epidermal necrolysis: results of an international prospective study. Arch
and glucose; however, its use in the paediatric population has Dermatol 2002;138:1019–24.
not yet been validated. 17 Naisbitt DJ, Pirmohamed M, Park BK. Immunopharmacology of hypersensitivity
reactions to drugs. Curr Allergy Asthma Rep 2003;3:22–9.
Recovery may be slow, taking several weeks, and may be even 18 Pavlos R, Mallal S, Phillips E. HLA and pharmacogenetics of drug hypersensitivity.
longer in TEN patients. Healing occurs leaving scars in mucosal Pharmacogenomics 2012;13:1285–306.
sites or hairy areas. Long-term sequelae may include hypopig- 19 Koh MJ, Tay YK. An update on Stevens-Johnson syndrome and toxic epidermal
mentation or hyperpigmentation changes, alopecia, anonychia, necrolysis in children. Curr Opin Pediatr 2009;21:505–10.
20 Chung WH, Hung SI. Genetic markers and danger signals in Stevens-Johnson
strictures or chronic ulcers in mucosal areas, and even impaired
syndrome and toxic epidermal necrolysis. Allergol Int 2010;59:325–32.
vision and blindness.26 21 Kaniwa N, Saito Y, Aihara M, et al. HLA-B locus in Japanese patients with
antiepileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal
necrolysis. Pharmacogenomics 2008;9:1617–22.
CONCLUSIONS 22 Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic
SJS and TEN are rare life-threatening conditions mostly attribu- epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803–13.
23 Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad
ted to drugs. An infectious origin may be responsible for several
Dermatol 2007;56:181–200.
SJS cases, but it may also act as a cofactor in other cases. In 24 Levi N, Bastuji-Garin S, Mockenhaupt M, et al. Medications as risk factors of
most paediatric patients, sulphonamides and anticonvulsants are Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled
the more likely drugs responsible, however, other drugs, such as analysis. Pediatrics 2009;123:297–304.
penicillins and NSAIDs may also be a potential threat. Early 25 Kunimi Y, Hirata Y, Aihara M, et al. Statistical analysis of Stevens-Johnson syndrome
caused by Mycoplasma pneumonia infection in Japan. Allergol Int
withdrawal of suspected drugs and a prompt admission to a spe- 2011;60:525–32.
cialised burn unit, with emphasis in nutritional support, have 26 Ferrándiz-Pulido C, García-Fernández D, Domínguez-Sampedro P, et al.
proved to improve survival rates. Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of
Drug therapy

the experience with paediatric patients in a university hospital. J Eur Acad Dermatol
Acknowledgements We wish to acknowledge Dr Amaya Viros (Signal Venereol 2011;25:1153–9.
Transduction Team, The Institute of Cancer Research, London, UK) for her critical 27 Forman R, Koren G, Shear NH. Erythema multiforme, Stevens-Johnson syndrome
review of the manuscript. and toxic epidermal necrolysis in children: a review of 10 years’ experience. Drug
Saf 2002;25:965–72.
Contributors Both authors contributed to conception and design of the
28 Halevy S, Ghislain PD, Mockenhaupt M, et al. EuroSCAR Study Group. Allopurinol is
manuscript, in drafting the article and final approval of the version to be published.
the most common cause of Stevens-Johnson syndrome and toxic epidermal
Competing interests None. necrolysis in Europe and Israel. J Am Acad Dermatol 2008;58:25–32.
Patient consent Obtained. 29 Spies M, Sanford AP, Aili Low JF, et al. Treatment of extensive toxic epidermal
necrolysis in children. Pediatrics 2001;108:1162–8.
Provenance and peer review Commissioned; externally peer reviewed. 30 Sheridan RL, Schulz JT, Ryan CM, et al. Long-term consequences of toxic epidermal
necrolysis in children. Pediatrics 2002;109:74–8.
31 Koh MJ, Tay YK. Stevens-Johnson syndrome and toxic epidermal necrolysis in Asian
REFERENCES children. J Am Acad Dermatol 2010;62:54–60.
1 Stevens AM, Johnson FC. A new eruptive fever associates with stomatitis and 32 Teraki Y, Murota H, Izaki S. Toxic epidermal necrolysis due to zonisamide associated
ophthalmia; report of two cases in children. Am J Dis Child 1922;24:526–33. with reactivation of human herpesvirus 6. Arch Dermatol 2008;144:232–5.
2 Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. 33 Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of the lymphocyte transformation
Br J Dermatol 1956;68:355–61. test in the diagnosis of drug sensitivity: dependence on its timing and the type of
3 Roujeau JC. The spectrum of Stevens-Johnson syndrome and toxic epidermal drug eruption. Allergy 2007;62:1439–44.
necrolysis: a clinical classification. J Invest Dermatol 1994;102:28S–30S. 34 Prendiville JS, Hebert AA, Greenwald MJ, et al. Management of Stevens-Johnson
4 Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic syndrome and toxic epidermal necrolysis in children. J Pediatr 1989;115:
epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch 881–7.
Dermatol 1993;129:92–6. 35 Sheridan RL, Weber JM, Schulz JT, et al. Management of severe toxic epidermal
5 Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson necrolysis in children. J Burn Care Rehabil 1999;20:497–500.
syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600–7. 36 Freiman A, Borsuk D, Sasseville D. Dermatologic emergencies. CMAJ
6 Sotelo-Cruz N. Stevens-Johnson syndrome and toxic epidermal necrolysis in children. 2005;173:1317–9.
Gac Med Mex 2012;148:265–75. 37 Fernando SL. The management of toxic epidermal necrolysis. Australas J Dermatol
7 Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativ 2012;53:165–71.
ummultiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in 38 Mayes T, Gottschlich M, Khoury J, et al. Energy requirements of pediatric patients
Germany (1990–1992): structure and results of a population-based registry. J Clin with Stevens-Johnson syndrome and toxic epidermal necrolysis. Nutr Clin Pract
Epidemiol 1996;49:769–73. 2008;23:547–50.
8 Goyal S, Gupta P, Ryan CM, et al. Toxic epidermal necrolysis in children: medical, 39 Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by
surgical, and ophthalmologic considerations. J Burn Care Res 2009;30:437–49. blockade of CD95 with human intravenous immunoglobulin. Science
9 Lam NS, Yang YH, Wang LC, et al. Clinical characteristics of childhood erythema 1998;282:490–3.
multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in Taiwanese 40 Stella M, Clemente A, Bollero D, et al. Toxic epidermal necrolysis and
children. J Microbiol Immunol Infect 2004;37:366–70. Stevens-Johnson syndrome: experience with high-dose intravenous immunoglobulins
10 García-Fernández D, García-Patos Briones V, Castells Rodellas A. Síndrome de and topical conservative approach. A retrospective analysis. Burns 2007;33:452–9.
Stevens/Johnson/necrólisis epidérmica tóxica. Piel 2001;16:444–57. 41 Mangla K, Rastogi S, Goyal P, et al. Efficacy of low dose intravenous
11 Ho JC, Ng PL, Tan SH, et al. Childhood linear IgA bullous disease triggered by immunoglobulins in children with toxic epidermal necrolysis: an open uncontrolled
amoxicillin-clavulanic acid. Pediatr Dermatol 2007;24:E40–3. study. Indian J Dermatol Venereol Leprol 2005;71:398–400.
12 Criado PR, Avancini J, Santi CG, et al. Drug reaction with eosinophilia and systemic 42 Shortt R, Gomez M, Mittman N, et al. Intravenous immunoglobulin does not
symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil
Isr Med Assoc J 2012;14:577–82. 2004;25:246–55.

1002 Ferrandiz-Pulido C, et al. Arch Dis Child 2013;98:998–1003. doi:10.1136/archdischild-2013-303718

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Review

43 Del Pozzo-Magana BR, Lazo-Langner A, Carleton B, et al. A systematic review 45 de Prost N, Ingen-Housz-Oro S, Duong Ta, et al. Bacteriemia in Stevens-Johnson
of treatment of drug-induced Stevens-Johnson syndrome and toxic epidermal síndrome and toxic epidermal necrolysis. Epidemiology, risk factors, and predictive
necrolysis in children. J Popul Ther Clin Pharmacol 2011;18: value of skin cultures. Medicine 2009;89:28–36.
e121–33. 46 Bastuji-Garin S, Fouchard N, Berocchi M, et al. SCORTEN: a severity of illness score
44 Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149–53.
Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on 47 Trent JT, Kirsner RS, Romanelli P, et al. Analysis of intravenous immunoglobulin for
patients included in the prospective EuroSCAR Study. J Am Acad Dermatol the treatment of toxic epidermal necrolysis using SCORTEN: the University of Miami
2008;58:33–40. Experience. Arch Dermatol 2003;139:39–43.

Drug therapy

Ferrandiz-Pulido C, et al. Arch Dis Child 2013;98:998–1003. doi:10.1136/archdischild-2013-303718 1003

 Downloaded from adc.bmj.com on June 12, 2014 - Published by group.bmj.com

A review of causes of Stevens−Johnson

syndrome and toxic epidermal necrolysis in
children
Carla Ferrandiz-Pulido and Vicente Garcia-Patos

Arch Dis Child 2013 98: 998-1003 originally published online July 19,
2013
doi: 10.1136/archdischild-2013-303718

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http://adc.bmj.com/content/98/12/998.full.html

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