ESPID Reports and Reviews

CONTENTS
Fever in StevensJohnson Syndrome and Toxic Epidermal Necrolysis

EDITORIAL BOARD
Co-Editors: Delane Shingadia and Nicole Ritz
Board Members
David Burgner (Melbourne, Cristiana Nascimento-Carvalho George Syrogiannopoulos
Australia) (Bahia, Brazil) (Larissa, Greece)
Kow-Tong Chen (Tainan,Taiwan) Ville Peltola (Turku, Finland) Tobias Tenenbaum (Mannhein, Germany)
Luisa Galli (Florence, Italy) Emmanuel Roilides (Thessaloniki, Marc Tebruegge (Southampton, UK)
Steve Graham (Melbourne, Greece) Marceline Tutu van Furth (Amsterdam,
Australia) Ira Shah (Mumbai, India) The Netherlands)

Fever in StevensJohnson Syndrome and Toxic Epidermal

Necrolysis in Pediatric Cases
Laboratory Work-up and Antibiotic Therapy
Maren Paulmann, PhD, and Maja Mockenhaupt, MD, PhD

Abstract: Fever is a symptom that often

accompanies skin eruptions, especially in
children. It can be a sign of an infectious
condition presenting with exanthems or it
may precede an exanthematous eruption.
Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) are severe
reactions affecting skin and mucosa with
blisters and erosions. High fever occurs
in these conditions, frequently before the
skin and/or mucosa is affected.
Key Words: StevensJohnson syndrome, toxic
epidermal necrolysis, erythema multiforme majus,
role of infections
Accepted for publication January 30, 2017.
From the Department of Dermatology, Dokumen-
tationszentrum schwerer Hautreaktionen (dZh),
Medical Center-University of Freiburg, Haupt-
strasse 7, 79104 Freiburg, Germany.
The RegiSCAR-study, in which all cases of the German
Registry of severe skin reactions (dZh) are included,
was funded by research institutions including DFG
and BMBF as well as various pharmaceutical com-
panies that provided unrestricted grants.
The authors have no conflicts of interest to disclose.
Address for correspondence: Maja Mockenhaupt,
MD, PhD, Department of Dermatology, Doku-
mentationszentrum schwerer Hautreaktionen
(dZh), Medical Center-University of Freiburg,
Hauptstrasse 7, 79104 Freiburg, Germany. E-mail:
dzh@uniklinik-freiburg.de.
Copyright 2017 Wolters Kluwer Health, Inc. All
rights reserved.
ISSN: 0891-3668/17/3605-0513
DOI: 10.1097/INF.0000000000001571
S tevensJohnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) are
rare, severe skin reactions characterized by
detachment of the epithelium of skin and
mucous membranes.1 These acute life-threat-
ening mucocutaneous reactions are accom-
panied by fever and flu-like symptoms, for
example, sore throat, headache and reduced
state of health.1,2
Traditionally, SJS/TEN has been classi-
fied into the erythema multiforme (EM) spec-
trum, because of similar histology, mucosal
involvement and presence of target-like
lesions. Therefore, many physicians equated
EM with mucosal involvement, that is, the
major type of EM or EM majus (EMM) with
SJS, mainly because the mucosal erosions in
both conditions cannot be differentiated. This
has led and still leads to confusion, especially
when the risk for mortality or recurrence is
evaluated. However, in a casecontrol study, it
has been shown that SJS/TEN and EMM are
distinct entities differing in their clinical pat-
tern of skin lesions, demographic data and eti-
ology.3 Furthermore, a positive Nikolsky sign
is an important clinical clue for differentiating
SJS/TEN and EMM.1,2 With the help of a con-
sensus classification, a diagnosis can be deter-
mined in more than 90% of the cases.4 SJS
and TEN are considered as 1 entity differing
in the extent of epidermal detachment related
to the body surface area (BSA): SJS, <10%
BSA; SJS/TEN overlap, 10%30% BSA;
TEN, >30% BSA. Hemorrhagic mucosal
erosions are found in SJS, SJS/TEN overlap,
but may be absent in some cases of TEN.5
Lesions in SJS/TEN are widespread, often
confluent purpuric macules (spots) or atypical
flat targets (without palpable edema or infil-
tration) on which blisters develop (Fig.1A).
In contrast, in EMM, typical (regular round
shape, well-defined border with 3 different
concentric zones) and/or atypical raised tar-
gets (poorly defined border, 2 zones) appear
mainly on the limbs (Fig.1B), sometimes also
on the face and trunk.3,4
Epidemiology and Etiology
The overall incidence of SJS/TEN has
been calculated as 1.51.8 cases per 1 million
inhabitants.6 However, the exact incidence for
children is still unknown. Preliminary data of
the German Registry of severe skin reactions
show that only 7% of the validated SJS/TEN
cases collected over 10 years are younger than
18 years of age with an almost equal distribu-
tion of gender. The mortality is about 6% and
much lower in the pediatric population than
in adults, as has been reported in small case
series.7 Recurrence of SJS/TEN has not been
observed except when the causative drug was
taken again. One might expect that SJS/TEN
induced by infection tends to reoccur, but this
has never been observed in more than 25 years
of the German Registry [unpublished data of
Dokumentationszentrum (dZh)]. In contrast,
recurrence is frequently seen in EM/EMM.

The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved
independently by the Editorial Board of ESPID.

The Pediatric Infectious Disease Journal Volume 36, Number 5, May 2017 www.pidj.com|513

Copyright 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Paulmann and Mockenhaupt The Pediatric Infectious Disease Journal Volume 36, Number 5, May 2017

is a prodromal or concomitant symptom of

SJS/TEN itself. In patients with no relevant
drug history, but an infection directly before
reaction onset, it is not easy to distinguish
whether the fever is due to the infection or
part of the reaction itself. However, fever
should be treated with antipyretic medication
as needed. Concerning the use of antibiotics
in SJS/TEN, a more differentiated approach
is recommended, because in drug-related
SJS/TEN, laboratory values for inflammation
parameters (leukocytes, C-reactive protein)
are often increased because of the reaction
itself. This is an unspecific increase, which
should not be treated preventively by anti-
biotics, because they may mask the occur-
rence of a real infection as a complication of
SJS/TEN.2,5 Parameters like procalcitonin or
sedimentation rate are usually normal. In our
experience of studying and treating patients
with SJS/TEN, fever and increased inflam-
mation parameters disappear or decrease
within a few days. If high fever and increased
inflammation parameters persist for more
than 5 days or clearly increase or rise again,
FIGURE 1. A: Confluent macules and atypical flat targets in SJS/TEN with developing a secondary infection may be present and
blisters followed by skin detachment. B: Typical targets with 3 concentric zones in appropriate investigations should be done,
EMM. C: Course of SJS/TEN. First symptoms of the reaction are unspecific like fever, for example, blood culture, radiogram, pol-
sore throat and reduced state of health (prodromal symptoms). Medications given ymerase chain reaction, procalcitonin and
for the prodromal symptoms are not associated with SJS/TEN even if the first clear urinary exam. Secondary infections more
sign (mucosal involvement, macules) appears after their intake (protopathic bias; 13 frequently affect patients with central venous
days). After admission, the progression of SJS/TEN to maximum skin detachment con- lines or mechanical ventilation and patients
tinues for up to 5 days (5D). in a state of immunosuppression.
In SJS/TEN induced by an infection,
SJS/TEN is mainly drug induced, and (Fig.1C; 1-3 D). Frequently, the drugs to the increase of inflammation parameters may
in approximately 65%75% of all cases, a treat these prodromal symptoms are accused be due to the infection and the reaction itself.
causative agent can be identified.5 In chil- to have caused the reaction, because they In such cases, it has to be clarified whether
dren and adolescents, certain antiepileptics, were taken shortly before the mucocutaneous the infection is viral or bacterial. Although a
antibacterial sulfonamides including sul- signs appear, which is actually after onset of specific pathogen may often not be detected,
fasalazine and far less frequently antibiotics the disease. This kind of misinterpretation of examinations for the following pathogens
(cephalosporins, macrolides and ampicillin) drug causality is called protopathic bias.2 should be done by polymerase chain reaction
have been identified to be the main causative For drugs with a confirmed risk for SJS/TEN, and/or serology: M. pneumoniae, Chlamydia
drugs.8,9 The preliminary data of the Ger- the time latency between beginning of drug pneumoniae, Streptococcus pneumoniae,
man Registry show that in no more than 50% use and onset of the reaction varies between EpsteinBarr virus, cytomegalovirus, herpes
of the pediatric cases, a causative drug was 4 days and 4 weeks. Furthermore, SJS/TEN simplex virus 1 and 2, human herpes virus 6
found. Many other cases seem to be induced occurs during the first continuous use of the and 7, influenza A and B, adenovirus, parvo-
by infection (eg, Mycoplasma pneumoniae, drug (without prior sensitization), whereas virus and coxsackie virus. In addition, radio-
Streptococci, cytomegalovirus, EpsteinBarr earlier well-tolerated use of the medication graph exam can be helpful, because some-
virus and other viruses) or have to be consid- does not suggest a causal relationship.5,10 times an infiltrate of the lung can be detected
ered as idiopathic. In such cases, we suggest In cases where drugs were taken to treat an even when other tests are negative. Any
to perform laboratory examinations to search infection in the corresponding period, the proven bacterial infection should be treated
for bacterial and viral pathogens. However, in infection, but also the newly introduced drug, with an antibiotic according to the pathogen
many cases, no pathogen can be detected. may be an etiologic factor (confounding by and to the resistogram or according to micro-
In numerous published case reports, indication).2 biologic treatment guidelines.11 Every anti-
antipyretics, analgesics or secretolytics are biotic can be used with 2 exceptions: (1) if
blamed for inducing SJS/TEN, although 2 an antibiotic is suspected to be the causative
large casecontrol studies could not detect Laboratory and Therapy drug, this agent should not be administered
an association.10 This is primarily due to a Fever up to 40C (104F) or even again and (2) if there is a known drug allergy
misunderstanding of how SJS/TEN starts higher occurs in nearly all patients with SJS/ to a certain antibiotic. In general, it is not
and develops (Fig.1C). Prodromal symp- TEN and is independent of the cause (drug vs. necessary to avoid a specific class of antibac-
toms such as fever, sore throat and flu-like infection).2,3 As shown in Figure1C, fever is terial agents, because cross-reactivity is not
symptoms, for which antipyretics, analgesics also present in patients without infection but a phenomenon observed in SJS/TEN. How-
and secretolytics are taken, appear 13 days with a clear causative drug, which was taken, ever, if a certain sulfonamide is thought to be
before the cutaneous and/or mucosal lesions for example, for 14 days. In such cases, fever the cause, other antibacterial sulfonamides

514 | www.pidj.com 2017 Wolters Kluwer Health, Inc. All rights reserved.

Copyright 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal Volume 36, Number 5, May 2017 Fever in SJS/TEN in pediatric cases
should be avoided. From our experience,
there is no correlation between the intake of
specific antibiotic(s) and a prolonged course
or a second event of SJS/TEN.
To date, there are no specific labora-
tory values to determine SJS/TEN, but certain
important values for the prognosis of mortality
have been summarized in a severity of illness
score for SJS/TEN (SCORTEN). SCORTEN
shows the best correlation as a severity marker
of SJS/TEN within the first 3 days after hospital
admission and includes 7 independent equiva-
lent factors: (1) age (40 years); (2) heart rate
(120/min); (3) underlying malignant disease;
(4) detachment of the BSA on the first day
(10%); (5) serum urea (10 mmol/L); (6)
serum bicarbonate (<20 mmol/L) and (7) serum
glucose (14 mmol/L).12 The higher the score
value, the poorer is the prognosis of the patient
and the higher is the risk of death. Although
SCORTEN was developed primarily for adults,
the prediction of morbidity in children and ado-
lescents is suitable. In a recent study, 4 predic-
tive models were examined not only for mor-
tality, which in children is usually lower than
predicted, but also for morbidity (mechanical
ventilation, days until wound healing, number
of infectious complications, number of acute
operations and length of stay). All models were
suitable for morbidity, but SCORTEN, specifi-
cally designed for SJS/TEN, was considered to
be more practicable than the others.13
Therapy of SJS/TEN remains unspe-
cific, and supportive treatment is crucial.1,2,5,11
In drug-related cases of SJS/TEN, the causative
drug should be discontinued immediately. In
infection-induced cases, the infection requires
adequate treatment, as explained above. For
topical treatment, antiseptic solutions or gels
should be used, and drug-free, nonadherent
wet gauze can be applied to areas affected
by blisters and erosions. Adequate analgesia
should be started, and if necessary, intrave-
nous fluids should be given, and the room
temperature should be raised. Furthermore, for
2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
mucosal erosions, local antiseptic treatment
is recommended. In case of ocular involve-
ment, a daily ophthalmologic consultation is
important, because the eye inflammation may
result in long-lasting sequelae.1,2 Systemic
immunomodulatory therapy with glucocorti-
costeroids and intravenous immunoglobulins
remains controversial, and data for both treat-
ments are ambiguous.1,11 Cyclosporine has
been used successfully in the treatment of SJS/
TEN, but further studies are needed, especially
in children and elderly patients.2
CONCLUSION
1. SJS/TEN and EMM are different entities
which can be distinguished by the clinical
pattern.
2. SJS/TEN in children and adolescents
is often not drug induced and probably
caused by infections or unknown factors
(idiopathic).
3. Fever is present and inflammation param-
eters are increased in SJS/TEN, independ-
ent of the etiology (medication, infection
and idiopathic).
4. Supportive therapy is the gold standard,
systemic immunomodulating therapy
remains controversial.
5. Preventative use of antibiotics is not rec-
ommended, but antibiotics should be given
in cases with a proven bacterial infection.
REFERENCES
1. Mockenhaupt M. Severe cutaneous adverse
drug reactions. In: Burgdorf WHC, Plewig G,
Wolff HH, et al. Braun-Falcos Dermatology.
Heidelberg: Springer; 2009:473484.
2. Paulmann M, Mockenhaupt M. [Schwere arz-
neimittelinduzierte Hautreaktionen: Klinik,
Diagnostik, tiologie und Therapie] Severe drug-
induced skin reactions: clinical features, diagno-
sis, etiology, and therapy. J Dtsch Dermatol Ges.
2015;13:625645.
3. Auquier-Dunant A, Mockenhaupt M, Naldi L,
et al; SCAR Study Group. Severe Cutaneous
Adverse Reactions. Correlations between clini-
cal patterns and causes of erythema multiforme
majus, Stevens-Johnson syndrome, and toxic epi-
dermal necrolysis: results of an international pro-
spective study. Arch Dermatol. 2002;138:1019
1024.
4. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical
classification of cases of toxic epidermal necroly-
sis, Stevens-Johnson syndrome, and erythema
multiforme. Arch Dermatol. 1993;129:9296.
5. Mockenhaupt M. The current understanding
of Stevens-Johnson syndrome and toxic epi-
dermal necrolysis. Expert Rev Clin Immunol.
2011;7:803813; quiz 814.
6. Rzany B, Mockenhaupt M, Baur S, et al.
Epidemiology of erythema exsudativum mul-
tiforme majus (EEMM), Stevens-Johnson syn-
drome (SJS) and toxic epidermal necrolysis
(TEN) in Germany (19901992). Structure and
results of a population-based registry. J Clin
Epidemiol. 1996;49:769773.
7. Hamilton GM, Fish J. Pediatric toxic epidermal
necrolysis: an institutional review of patients
admitted to an intensive care unit. J Burn Care
Res. 2013;34:e351e358.
8. Quirke KP, Beck A, Gamelli RL, et al. A 15-year
review of pediatric toxic epidermal necrolysis. J
Burn Care Res. 2015;36:130136.
9. Levi N, Bastuji-Garin S, Mockenhaupt M,
et al. Medications as risk factors of Stevens-
Johnson syndrome and toxic epidermal necroly-
sis in children: a pooled analysis. Pediatrics.
2009;123:e297e304.
10. Mockenhaupt M, Viboud C, Dunant A, et al.
Stevens-Johnson syndrome and toxic epider-
mal necrolysis: assessment of medication risks
with emphasis on recently marketed drugs.
The EuroSCAR study. J Invest Dermatol.
2008;128:3544.
11. Ghislain PD, Roujeau JC. Treatment of severe
drug reactions: Stevens-Johnson syndrome, toxic
epidermal necrolysis and hypersensitivity syn-
drome. Dermatol Online J. 2002;6:5.
12. Bastuji-Garin S, Fouchard N, Bertocchi M, et
al. SCORTEN: a severity-of-illness score for
toxic epidermal necrolysis. J Invest Dermatol.
2000;115:149153.
13. Beck A, Quirke KP, Gamelli RL, et al. Pediatric
toxic epidermal necrolysis: using SCORTEN
and predictive models to predict morbidity when
a focus on mortality is not enough. J Burn Care
Res. 2015;36:167177.
www.pidj.com | 515