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194]

Review Article

Stevens‑Johnson Syndrome and Toxic Epidermal Necrolysis in Children

Abstract Sudip Das,

SJS and TEN are diseases characterised by epidermal detachment and necrolysis predominantly of Ramkumar
drug induced etiology. SJS/TEN begins with a prodrome of fever, malaise, anorexia, pharyngitis, and Ramamoorthy1
headache lasting for 2-3 days, at times, extending to 10-11 days. Mucosal lesions usually precede
Department of Dermatology,
skin lesion. Usually, two mucosal membranes are involved, most commonly conjunctiva and oral
Calcutta National Medical
mucosa. Oral mucosal involvement is seen in 90% of SJS and almost all patients diagnosed with College, Kolkata, West Bengal,
TEN. In SJS, mucosal involvement is widespread and confl uent in contrast to erythema multiforme 1
Department of Dermatology,
where it is focal and seen in only 25%-60% of cases. The exact pathogenesis of SJS and TEN is not Kanchi Kamakoti Child Trust
fully elucidated. In view of the paucity of T-cell infiltrate,keratinocyte apoptosis could be the result Hospital, Chennai, Tamil Nadu,
of autocrine or paracrine interaction between Fas, a death receptoron keratinocyte and Fas Ligand India
(FasL) produced by the keratinocytes along with the substantial contributionof soluble FasL from
peripheral mononuclear cells. FasL upregulation in keratinocytes is nitric oxide-dependent anddriven
by T-cell derived tumor necrosis factor (TNF) alpha and Interferon-gamma.The management revplves
around immediate stoppage of drug and.,supportive care .IVIG,corticosteroids and cyclosporine are
all effective drugs but no RCT is available for any of them

Keywords: Children, Stevens‑Johnson syndrome, toxic epidermal necrolysis

Introduction purpuric macules or flat atypical target

Stevens‑Johnson syndrome  (SJS) was first
described by the two pediatricians (A. M.
Stevens and F. C. Johnson) in 1922 in the
New York city in two children in whom
the illness was most likely triggered by
infection.[1] In 1956, A. Lyell used the
term toxic epidermal necrolysis (TEN) to
describe the chafed‑looking skin lesions in
four of his patients, based on the belief that
these lesions were induced by a circulating
toxin. TEN was also independently
described by Lang and Walker in 1956.[2]
Definition
SJS and TEN are considered to be
variants of the same pathologic process.
A  classification scheme based on the
severity of epidermal detachment at the
worst stage of the disease was described
by Bastuji‑Garin et  al.[3] The following
categories are included:
1. Bullous erythema multiforme ‑
lesion in addition to blisters and erosions
in 1 or more mucous membranes
3. Overlap SJS‑TEN ‑ detachment between
10% and 30% of BSA plus widespread
erythematous or purpuric macules or
atypical target‑like annular patches
4. TEN with spots‑detachment of above
30% of BSA plus widespread purpuric
macules or atypical target lesions and
5. TEN without spots‑detachment in large
epidermal sheets and above 10% of
BSA without purpuric macules or target
lesions.
Raised atypical target lesions  (ill‑defined,
round palpable lesions with only two
zones (central raised edematous area
with an erythematous border) should be Address for correspondence:
differentiated from target lesions which Dr. Sudip Das,
are round, sharply demarcated lesions Department of Dermatology,
Calcutta National Medical
comprising three zones [Figure 1]. Flat College, Kolkata, West Bengal,
atypical target lesions‑ill‑defined, with only India.
two nonpalpable zones, central may be E‑mail: sudipderma@gmail.com

Localized “typical targets” or “raised blistered [Figure 2].

atypical target lesions” with epidermal
Clinical Features Access this article online
detachment below 10% of body surface
area (BSA) SJS/TEN begins with a prodrome of Website: www.ijpd.in

2. SJS ‑ detachment below 10% of BSA fever, malaise, anorexia, pharyngitis, DOI: 10.4103/ijpd.IJPD_120_17

plus widespread erythematous or and headache lasting for 2–3 days, at Quick Response Code:

This is an open access article distributed under the terms of the

Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0
License, which allows others to remix, tweak, and build upon the
work non‑commercially, as long as the author is credited and the
new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com
How to cite this article: Das S, Ramamoorthy R.
Stevens-johnson syndrome and toxic epidermal
necrolysis in children. Indian J Paediatr Dermatol
2018;19:9-14.

© 2017 Indian Journal of Paediatric Dermatology | Published by Wolters Kluwer - Medknow 9

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Das and Ramamoorthy: SJS –TEN in pediatric age group
Figure 1: Classical target lesions with 3 zones
times, extending to 10–11 days. Mucosal lesions usually
precede skin lesions. Usually, two mucosal membranes are
involved, most commonly conjunctiva and oral mucosa.[4]
Oral lesions occur in crops. Thickly walled vesicles rupture
into irregularly shaped ulcers covered by pseudomembranes
are seen in lips, buccal mucosa, palate, the anterior, and
lateral border of the tongue. Gums are spared in contrast
to herpetic gingivostomatitis. Oral mucosal involvement is
seen in 90% of SJS and almost all patients diagnosed with
TEN.[5] In SJS, mucosal involvement is widespread and
confluent in contrast to erythema multiforme where it is
focal and seen in only 25%–60% of cases.[5]
Skin lesions are accompanied by pain, which is a
characteristic feature of SJS and TEN. Flat atypical target
lesions or erythematous macules of irregular shape and
size with are seen. Skin lesions are seen initially on the
face, neck, chest, trunk, and proximal extremities. This is
followed by confluence and development of flaccid blisters.
SJS should be differentiated from erythema multiforme
major which is recognized by the presence of acrally
distributed typical target lesions, and are not associated
with significant skin detachment.[6]
Early detection of pulmonary complications requires a high
degree of clinical suspicion. Children may present with
dyspnea, bronchial hypersecretion, hypoxemia, and sloughing
of the bronchial mucosa are seen in the acute stage of the
illness. Chest radiography may not show any abnormality
or may reveal interstitial infiltrates.[7] Delayed complications
include pneumonitis, atelectasis, and pneumothorax.[8]
Other complications of SJS and TEN include
microalbuminuria and presence of renal tubular enzymes in
urine, arthralgia, hepatitis, encephalopathy, and myocarditis.[9]
Etiology
SJS is very rarely seen in very young children. This may
also be due to less possibility for exposure to potentially
Indian Journal of Paediatric Dermatology | Volume 19 | Issue 1 | January-March 2018
Figure 2: Atypical target lesions with 2 zones
sensitizing drugs in this age group. However, the incidence
of skin reaction to lamotrigine in children is 1:100,
comparatively much higher than the reported incidence of
1:1000 in adults. Concomitant administration of valproic
acid and faster dose escalation are the risk factors for
developing adverse drug reaction to lamotrigine.[9,10]
Drugs are implicated in the majority of adults and
children with SJS or TEN.[7] A thorough search for the
intake of drugs within 8 weeks before the onset of the
rash is mandatory. Common drugs that are known to
cause pediatric SJS and TEN are included in Table 1.
It is noteworthy that antibiotics are a leading cause
of drug‑induced SJS in children, whereas allopurinol,
nevirapine, and piroxicam are uncommon causes. However,
infections could play a major role in triggering SJS in
children, outnumbering drug‑induced cases in some studies.
[11]
Mycoplasma pneumonia is implicated as an etiological
factor in SJS, especially in children who present with
mucosal lesions and limited skin involvement. Pulmonary
involvement is a common associated feature in mycoplasma
pneumonia triggered SJS or TEN.[12] Other triggers include
herpes simplex virus, streptococci, cytomegalovirus, live
virus vaccinations, and DPT vaccination.
Pathophysiology
The exact pathogenesis of SJS and TEN is not fully
elucidated. In view of the paucity of T‑cell infiltrate,
keratinocyte apoptosis could be the result of autocrine
or paracrine interaction between Fas, a death receptor
on keratinocyte and Fas Ligand (FasL) produced by the
keratinocytes[13] along with the substantial contribution
of soluble FasL from peripheral mononuclear cells. FasL
upregulation in keratinocytes is nitric oxide‑dependent and
driven by T‑cell derived tumor necrosis factor (TNF) alpha
and Interferon‑gamma.[12]
Drug‑specific CD8+  cytotoxic T‑cells release perforins and
granzyme on direct contact with keratinocytes expressing
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Das and Ramamoorthy: SJS –TEN in pediatric age group

specific  MHC  alleles is also a possible mechanism for
the development of drug‑induced SJS and TEN. Many
publications have confirmed the strong association between
Carbamazepine‑induced SJS and HLA‑B*15:02 as well as
HLA‑B*57:01and abacavir hypersensitivity. The predictive
value testing of HLA‑B*15:02 in Indian population is
supported by two recently conducted studies. The positive
predictive value of the presence of HLA‑B*15:02 in
predicting SJS/TEN following usage of carbamazepine
ranges from 3% to 7.7%.[13]
An overwhelming body of evidence points out to the
role of granulysin in the pathogenesis of SJS and TEN.
Granulysin is a protein expressed in two isoforms (15 KDa
and 9  KDa), produced by CD8+  Cytotoxic T‑cells,
natural killer T‑cells and natural killer cells. Granulysin
is detected at much higher levels in blister fluid of TEN
than FasL, granzyme, and perforin.[14] High serum levels
of granulysin were found in SJS and TEN 2–4 days before
the development of skin lesions. This is in contrast to the
declining levels of soluble FasL about 3–6 days following
clinical course of SJS and TEN. Soluble FasL is secreted
by monocytes and keratinocytes and increases before the
development of skin lesions. Moreover, FasL was found
to elevated in patients diagnosed with the drug‑induced
maculopapular exanthematous eruption.[15]
Keratinocyte apoptosis can also be mediated by annexin‑1
receptor on monocytes interacting with formyl peptide
receptor 1 on keratinocytes leading to necroptosis, a form
of cell death.[16]
High mobility group B protein (HMGB1) is considered to
play a central role in the pathogenesis of SJS and TEN. This
protein functions as a transcription factor intracellularly and as
an activator of inflammatory cascade extracellularly. HMGB1
levels can be estimated by means of an immune assay, and it
remains elevated for a longer time than granulysin.[7]
Interleukin 15 (IL‑15) levels correlated with disease
progression and mortality associated with SJS and TEN.
IL‑15 may play a pivotal role in the pathogenesis of SJS
and TEN. IL‑15 induces the expression of granulysin and
enhances the activity of NK cell and CD8+  cytotoxic
T‑cells.[17]

Table 1: Drugs causing Stevens‑Johnson syndrome and
toxic epidermal necrolysis in children
Category Names of the drugs
Antibiotics Penicillins, cephalosporins, sulfonamides,
macrolides, fluoroquinolones
Antiepileptics Carbamazepine, phenytoin, phenobarbitone,
valproic acid, lamotrigine
Miscellaneous Nonsteroidal anti‑inflammatory drugs (excluding
oxicams), paracetamol, nimesulide
Others Allopurinol, nevirapine, ayurvedic and
homeopathic medicines
Diagnosis
The diagnosis of SJS and TEN is based on clinical findings.
Histopathology is not specific  [Figure 1]. Skin biopsy and
immunofluorescence may be required in special situations to
rule other diseases which have a similar clinical presentation
[Table 2].[19] Investigation for coexistent drug rash with
eosinophilia and systemic symptoms is recommended.[18]
Prognosis
Score of ten (SCORETEN) is a severity of illness score
specific for SJS and TEN [Table 3]. It is a useful tool for

Table 2: Differential diagnosis of Stevens‑Johnson syndrome/toxic epidermal necrolysis

Disorder
Staphylococcal scalded skin
syndrome
Acute generalized
exanthematous pustulosis
Generalized bullous drug fixed
drug eruption
Paraneoplastic pemphigus
Acute graft versus host
reaction
Linear IgA bullous disease
BSLE
BSLE ‑ Bullous SLE; SLE ‑ Systemic lupus erythematosus; TEN ‑ Toxic epidermal necrolysis; IgA ‑ Immunoglobulin A
Context Dermatological features Pathology Etiology
Infants No mucous membrane involvement, Subcorneal detachment Staphylococcus
perioral and flexural involvement, toxins
Nikolsky’s sign in involved and
apparently normal skin
Recent drug intake Pustules Subcorneal pustules Medications
Older children Well demarcated large blisters with Often indistinguishable from Medications
absent or mild mucosal involvement TEN
Lymphoma Severe mouth lesions, slower Acantholysis, positive Autoimmunity
progression findings in direct
immunofluorescence study
Bone marrow Slower progression, liver and gut Very similar to TEN Alloimmunity
transplantation involvement
Drug intake Tense blisters Subepidermal blister, Medications
positive findings in direct
immunofluorescence study
Features of SLE Photodistribution, slower Subepidermal blister, Autoimmunity
progression positive findings in direct
immunofluorescence study

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Das and Ramamoorthy: SJS –TEN in pediatric age group
Table 3: SCORETEN
Prognostic factors Points SCORTEN Mortality
rates (%)
Ag e >40 (years) 1 0-1 3.2
Heart rate >120/ms 1 2 12.1
Cancer or hematological 1 3 35.8
malignancy
>10% body surface area 1 4 58.3
Serum urea >10 mmol/L 1 >5 90
Bicarbonate <20 mmol/L 1
Serum glucose >14 mmol/L 1
SCORTEN ‑ Score of toxic epidermal necrolysis
predicting the mortality and is calculated on day 1 and day
3 of the illness. The usefulness of SCORTEN in childhood
SJS and TEN has been validated in a recently published
study.[20]
In general, the mortality of SJS is <5%, whereas around
30% of patients diagnosed with TEN die during the acute
stage of the illness.[21]
Management
Early withdrawal of the offending drug and is found to
improve the overall prognosis. This is especially in SJS/
TEN triggered by drugs which have a short elimination
half‑life. Concomitant administration of medications known
to decrease the elimination of the offending drug should be
discontinued.
Supportive care forms the cornerstone of therapy. In SJS
and TEN, superior results were obtained by supportive
care alone compared to administration of glucocorticoids
or Intravenous immunoglobulin (IVIG), in reducing the
associated mortality. Early referral of the child to the
intensive care unit or to a center specialized in caring for
burns is required. Children may refuse to void due to pain
resulting from urethritis or balanitis or vulvovaginitis,
requiring the need for catheterization. Feeding by
nasogastric tube is often required. Careful adherence to oral
hygiene is needed to avoid superinfection.[18]
Nutritional requirements of the child are to adequately
taken care off. The following formula is useful in
calculating the daily energy requirements of a child with
SJS or TEN. Energy requirements (in calories) for pediatric
SJS/TEN patients is estimated by the following equation.[22]
Daily requirement in calories = (preinjury weight [kg] ×
9 24.6) + (wound size [% of BSA] ×4.1) +940 calories.
Fluid requirements are about 30% lower than that required
for patients with burns.
Care of the Skin
Extensive debridement is not advisable in children. The
detached epidermis can be left over and would often serve
as a biological dressing. In children who have extensive
Indian Journal of Paediatric Dermatology | Volume 19 | Issue 1 | January-March 2018
skin necrosis, gentle cleansing followed by biological
dressing is recommended. Maintaining room temperature
at 30°C–32°C is recommended in addition to strict aseptic
precautions, maintenance of fluid, acid‑base and electrolyte
balance.
Swabs for bacterial culture and sensitivity should
be performed at regular intervals (preferably once
in every 3rd day) along with periodic blood culture.
Staphylococcus aureus is the commonest cause of
superinfection in early stage followed by Pseudomonas
aeruginosa in the late stages of SJS. The negative predictive
value of skin cultures for sepsis has been emphasized in a
recently published work by de Prost et al.[23]
Care of the Genitalia
Daily inspection of genitalia is needed during the acute
stage of the illness. Vaginal synechiae, and vaginal
adenosis are among the well‑known complications of SJS
and TEN. Vulval erosions can be treated with judicious
usage of topical steroids belonging to group three of the
potency chart for topical steroids  (fluticasone propionate
ointment, betamethasone valerate 0.1% or betamethasone
dipropionate 0.05%). Menstrual suppression is a yet another
option which can be considered in female adolescents.
Urethral metal stenosis is a long‑term genital complications
in male children.[24]
Care of the Eyes
Immediate consultation with ophthalmologist is mandatory
in a child diagnosed with SJS or TEN. The ocular
complications of SJS and TEN may either accompany or
follow the skin lesions. Ocular involvement is reported in
75% of cases.[25]
Ophthalmological follow‑up during acute phase of the
disease is also recommended.[6] Ocular complications
include mucopurulent conjunctivitis in the acute stage
followed by long‑term complications such as dry eye,
synechiae, symblepharon, and trichiasis.[8] Visual loss
secondary to corneal scarring and vascularization is the
most dreaded long‑term ocular complication of SJS and
TEN. Eye care includes the use of preservative‑free
lubricant eye drops, daily removal of pseudomembranes,
daily breaking of synechiae, topical corticosteroids, and
laser hair removal for trichiasis.[26]
Systemic Therapy
Corticosteroids, IVIG, cyclosporin, TNF blockers have all
been used in the management of SJS and TEN.[18,27] None
of them have been tested by randomized control trials. The
severity and rarity of the condition precludes the possibility
of conducting randomized controlled trials in this disorder.
Based on the published studies, no definite conclusion
could be made regarding the efficacy of systemic steroids
in reducing the mortality and morbidity of SJS and TEN.[28]
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Das and Ramamoorthy: SJS –TEN in pediatric age group
IVIG should be administered early in the course of the
illness, preferably within 48 h of onset of clinical disease[29]
at a total dose of 3 g/kg over a period of 3–5 days.[29] Kim
et  al.[30] noticed improvement in ocular outcome, if IVIG
is given within 6 days of disease onset. Similarly, good
results in ocular complications were obtained if systemic
steroids were instituted within 6 days of symptom onset.[30]
However, neither IVIG nor steroids influenced the overall
mortality rate of SJS or TEN based on SCOTEN scoring.[30]
A tendency toward reduction in recovery time following
usage of a combination of IVIG with systemic steroids
was observed in a recently published meta‑analysis.
Cyclosporine is given at 3–6 mg/kg for 1 week followed
by a tapering course. In a retrospective study,[31]
cyclosporine gave superior results in terms of improvement
in mortality when compared to IVIG.[32] However, the
results could be confounded by the fact that the group of
patients who received cyclosporine were relatively more
healthy.[33] A recent meta‑analysis comparing cyclosporine
with other immunomodulators showed a consistent effect
of cyclosporine on the reduction of mortality associated
with SJS and TEN.[34]
Conclusion
Childhood SJS and TEN are diseases associated with
high mortality and significant long‑term morbidity. Early
diagnosis, immediate referral to an intensive care center for
supportive care and dedicated effort by a multidisciplinary
team of experts form the pillars of treatment. In
resource‑poor setting, corticosteroids started earlier are a
good alternative to both cyclosporine and IVIG.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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