Stevens-Johnson Synd

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Stevens-Johnson Syndrome m)
December 01, 2008 | Pediatric Skin Diseases [1], Bacterial Conjunctivitis [2]
By Helene Tigchelaar, MD [3], Nirupama Kannikeswaran, MD [4], and Deepak M. Kamat, MD, PhD [5]

A 13-year-old boy was brought to the emergency department (ED) with a generalized itchy rash of 2
days' duration. For the past 3 days, he had dry, itchy eyes with a purulent discharge (Figure 1) and
nonbilious emesis 2 or 3 times per day, with some blood streaks in the vomitus on the third day of
illness.

A 13-year-old boy was brought to the emergency department (ED) with a generalized itchy rash of 2
days' duration. For the past 3 days, he had dry, itchy eyes with a purulent discharge (Figure 1) and
nonbilious emesis 2 or 3 times per day, with some blood streaks in the vomitus on the third day of
illness. Chills developed on the third day, but the patient's temperature was not measured. His lips
were swollen and cracked (Figure 2), which made it painful to eat or drink. About 6 months earlier,
he had a similar episode that resolved with application of a topical cream to the lips. He also had
painful urination without urgency or penile discharge. He denied recent use of medications and had
no ill family members. He had been well before the onset of symptoms.

Figure 1 About 30% of children with Stevens-Johnson syndrome have ocular involvement. This
13-year-old boy had mucopurulent conjunctivitis with episcleritis as a manifestation of the disease.

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Figure 2 Mucositis of the lips in this teenager was a manifestation of Stevens-Johnson syndrome.
Oral lesions are the most common type of mucosal involvement in affected patients. They are
extremely painful and limit oral intake.

The teenager was apathetic, mildly dehydrated, and appeared to be in pain. Oral temperature was
39.6C (103.2F); respiration rate, 20 breaths per minute; heart rate, 108 beats per minute; and
blood pressure, 108/63 mm Hg. Physical examination revealed injection of the conjunctivae with
sticky yellow discharge, swollen lips with erosion of the mucosa, hemorrhagic crusting, intraoral
ulcers, dry oral mucous membranes, ulceration of the head of the penis, and a generalized rash that
consisted of target lesions with central erosions.
The white blood cell count was normal (6700/L), without a left shift; hemoglobin level was 14.3
g/dL. Results of coagulation studies were normal. The erythrocyte sedimentation rate and C-reactive
protein level were markedly elevated (107 mm/h and 33.78 mg/L, respectively). Serum electrolyte
levels were normal, blood urea nitrogen level was elevated (33 mg/dL), and creatinine level was 1.3
mg/dL. Liver function test results were normal; the albumin level was slightly below normal (3.3
g/dL). Urinalysis results showed a specific gravity of 1.028 and 1+ protein; all other parameters were
within normal range. IgA was 183 mg/dL. Direct fluorescent antibody studies of lip vesicles for
herpes simplex virus types 1 and 2 were negative. Fluorescein examination of the eye demonstrated
no corneal uptake of dye. A blood sample for culture was obtained.
In the ED, the patient received intravenous saline, ceftriaxone (a single dose), acyclovir,
diphenhydramine, and analgesia. A topical analgesic was applied to the ulcerated mouth, and
emollients were applied to the rash. The ophthalmology consultant diagnosed mucopurulent
conjunctivitis with episcleritis and recommended lubrication with artificial tears and erythromycin
ophthalmic ointment. The dermatology consultant performed a biopsy of a target lesion, which
demonstrated interface dermatitis with vacuolation of the basal layer and rare dyskeratotic cells in
the epidermis suggestive of Stevens- Johnson syndrome (SJS) or erythema multiforme (EM).
Serological test results were negative for Mycoplasma; herpes simplex virus; Epstein-Barr virus;
Cytomegalovirus; HIV; hepatitis A, B, and C viruses; and Treponema pallidum. Blood culture was
negative.

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Because of persistent vomiting and a steadily increasing elevated lipase level (fromConsultantLive
713 U/L to a (ht
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maximum of 1589 U/L), abdominal ultrasonography was performed. The size of the pancreas was at
the upper limits of normal; there was a small amount of free fluid in the abdomen. sconsultantlive.co
m) he was able
During the patient's 10-day hospitalization, intravenous hydration was maintained until
to tolerate oral feeds. At discharge, the eye and skin lesions had completely resolved and the oral
ulcers had almost completely healed. The final diagnosis was SJS and acute pancreatitis.

(Discussion on next page.)

EM MAJOR: AN OVERVIEW
SJS and toxic epidermal necrolysis (TEN) are severe mucocutaneous blistering disorders of acute
onset that are associated with considerable morbidity and life-threatening complications. Like EM
minor, both SJS and TEN may have oral mucosal lesions and ulcerated lesions; however, SJS and TEN
are distinguished from EM by the involvement of 2 or more mucosal surfaces, more widespread
lesions, systemic illness, and more extensive epidermal involvement on biopsy.
von Hebra1 first described EM as a self-limited disease in healthy young adults that is most
commonly caused by herpes simplex virus, has the classic iris or target lesion, and is rarely
associated with fever or systemic symptoms. Stevens and Johnson2 later described a severe,
generalized skin infection, prolonged high fever, purulent conjunctivitis, and severe oral stomatitis in
2 children. They excluded the diagnosis of EM in these 2 children because of the presence of atypical
target lesions and prolonged systemic symptoms.
The term "EM minor" became synonymous with von Hebra disease and "EM major" (EM with
involvement of 2 mucous membranes) with SJS. TEN, first described by Lyell,3 is currently
considered to be a severe form of SJS caused by a similar spectrum of drugs and characterized by
full-thickness epidermal loss over a large extent of the body surface. The current thinking is that
there are 2 groups of diseases:
EM and bullous EM are primarily caused by herpes simplex virus, present with classic target lesions
in an acral distribution, and have a benign course.
SJS and TEN are often druginduced, are characterized by the presence of atypical target lesions and
purpuric macules, and cause severe morbidity.

The current classification of acute severe bullous disorders comes from Bastuji-Garin and colleagues4
and is based on the extent of body surface involvement and type of skin lesions. SJS has an
estimated incidence of2.6 cases per million per year5 and affects all age-groups.
ETIOLOGY
Drugs are the most common cause of SJS and TEN,6 although infectious agents and immunizations
have also been implicated. Drugs that frequently cause SJS include antibiotics (particularly
sulfonamides, aminopenicillins, and cephalosporins) and aromatic anticonvulsants- phenobarbital,
phenytoin, and carbamazepine. 7 While NSAIDs and antigout medications frequently cause SJS in
adults, they are rarely implicated in children. Drug-induced SJS typically occurs between 1 and 3
weeks of initiation of drug therapy. Persons with systemic lupus erythematosus and those who are
infected with HIV are more susceptible to drug-induced SJS.
Among infectious causes, herpes simplex virus and Mycoplasma pneumoniae are most strongly
associated with SJS. Epstein-Barr virus, Cytomegalovirus, and streptococcal infections are also
associated with SJS. Herpes simplex virus 1 infection was the suspected cause of SJS in this patient
based on the presence and previous episode of lip lesions. However, given the negative serological
results, this could not be proved conclusively.
PATHOGENESIS
SJS is believed to be an immunological disorder that causes perivasculitis of the superficial dermal
vessels. Immunofluorescent examination of early skin lesions in SJS demonstrate IgM and C3
deposits in the vascular walls in most patients. Other histological changes include full-thickness
necrosis of the epidermis and a scant mononuclear cell in the dermis. The dermoepidermal junction
shows changes that range from vacuolar alteration to subepidermal blister formation. In the
drug-induced form, it is believed that full-thickness epidermal necrosis is triggered by accumulation
of the drug metabolites in the epidermis. Patients and their first-degree relatives are believed to
have genetic defects in the drug metabolic pathway that leads to accumulation of the drug
metabolites. Persons with HLAB12 (HLA-Bw44) antigen are at greater risk for the development of
SJS.8 CD8+ T-cellmediated cytotoxicity is believed to be responsible for the epidermal necrosis in

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TEN. ConsultantLive (ht
CLINICAL FEATURES tp://www.pediatric
SJS is usually preceded by a prodrome of fever, sore throat, and generalized malaisesconsultantlive.co
that lasts for
m) is prescribed.
several days and is often misdiagnosed as an infectious illness for which an antibiotic
In a large case series from Toronto, 61% of children had mucous membrane involvement, most
commonly oral, genital, and anal.9 Of those children, 95% had oral lesions that ranged from isolated
vesicles or bullae to swelling, blistering, and ulceration of both lips. The mouth lesions seen in SJS
are extremely painful and limit oral intake, as was the case in this patient.
Genital lesions include vesicobullous vulvovaginitis, ulcers, and anal and urethral erosions. About
30% of children have ocular involvement in the form of hemorrhagic conjunctivitis, corneal
ulceration, blepharitis, or scleritis.9 These can lead to corneal erosions, pseudomembrane formation,
and adhesions. Rarely, other mucous membranes, such as the esophagus, intestinal tract,
respiratory epithelium, and nasal cavity, can also be affected.
The rash of SJS usually begins as purpuric macules that evolve within days into atypical targetlike
bullae and erosions of the face, trunk, limbs, palms, and soles. The scalp is usually spared. Typical
target lesions are usually less than 3 cm in diameter and round with a well-defined border. They
have 3 zones with 2 concentric rings, 1 of which is palpably edematous and paler than the central
disk. Atypical target lesions are also round, edematous, palpable lesions but have only 2 zones and
an ill-defined border.
The rash tends to be more severe and extensive in patients with drug-induced SJS. It can progress to
sheetlike loss of epidermis, especially in cases of TEN. The Nikolsky sign (formation of a blister with
peeling of the superficial layers of skin from the lower layers, leaving wet, red, painful areas on
application of horizontal, tangential pressure to the skin) is usually positive in TEN. The average
duration of illness is usually 2 weeks. Resolution and healing occur between 1 and 2 weeks.

(Discussion continues on next page.)

LABORATORY FINDINGS
SJS is usually a clinical diagnosis. Abnormal laboratory findings may include an elevated
sedimentation rate, hypoalbuminemia (as in this patient), mildly elevated liver enzyme levels,
microscopic hematuria, and mild leukocytosis. Leukopenia is considered a poor prognostic sign and
may indicate superinfection and sepsis. Serological test results may be positive in
Mycoplasma-induced SJS.
A skin biopsy is indicated only when the diagnosis is uncertain. Histopathological findings include a
mononuclear perivascular cell infiltrate in the dermis, basal layer edema, subepidermal blister
formation, and epidermal cell necrosis. TEN is characterized by epidermal necrosis with minimal
evidence of inflammation.
COMPLICATIONS AND SEQUELAE
A mortality rate of up to 5% has been reported with SJS.10 Patient age and extent of skin detachment
have been proposed as the main prognostic factors. Early withdrawal of the causative agent, when
one is involved, may decrease mortality. 11 The most common complication is sepsis (most often
caused by Staphylococcus aureus followed by Pseudomonas aeruginosa).
Hypovolemic shock can occur from fluid loss and electrolyte imbalance secondary to extensive skin
detachment. Sloughing and edema of the respiratory epithelium may lead to upper airway
obstruction, pneumonia, or diffuse interstitial pulmonary disease. Urethral erosions can cause acute
urinary retention, especially in younger children. GI erosions can lead to upper GI bleeding and
bloody diarrhea. Less common sequelae include cutaneous scarring, palpebral synechiae with
permanent visual impairment, and bronchiolitis obliterans.
In a review of the literature, there was no reported association between pancreatitis and SJS,
although some of the drugs that cause SJS (such as valproic acid) also cause pancreatitis. We do not
believe that the pancreatitis led to SJS in this patient.
MANAGEMENT
SJS and TEN in children are dermatological emergencies. Diagnosis should prompt immediate
discontinuation of all potential causative drugs. Older children with proven Mycoplasma infection can
be treated with either an oral macrolide or oral doxycycline. Patients with extensive blistering or skin
loss require care at a pediatric burn center. Those with extensive skin detachment require reverse
barrier isolation and a sterile environment. Consultation with an ophthalmologist and dermatologist
is recommended.
Supportive measures include isolation, fluid and electrolyte balance, nutritional support, eye and

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mouth care, pain management, and nonadherent protective dressings for skin lesions. ConsultantLive
12
Because of(ht
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poor oral intake, many children require nutritional support with either a nasogastric tube or
sconsultantlive.co
parenteral alimentation for 1 to 2 weeks. While surgeons advocate extensive debridement, as in a
burn patient, dermatologists recommend debridement of necrotic and peeled skin only. m) The value of
topical antibiotics is unproved. No particular type of dressing (synthetic, biological, or petrolatum
gauze) has been proved superior. Children often require an opioid analgesic for dressing changes.
Other than good supportive care, there is no effective and universally accepted treatment of SJS.
Although prevention and early treatment of sepsis is indicated, prophylactic antibiotics are not
recommended.
The role of corticosteroids in the treatment of SJS or TEN is controversial. Although earlier
retrospective studies reported a longer hospital stay and a higher incidence of complications in
children with SJS who were treated with corticosteroids, 13 other studies reported an outstanding
success rate with early and prompt treatment with highdose corticosteroids.14 To date, no
randomized controlled studies have shown a benefit from their use in the treatment of SJS.
Moreover, SJS can be managed successfully with supportive care alone.12
Although some case series reported improved outcomes in patients with SJS after a single infusion of
intravenous immunoglobulin (IVIG),15,16 a prospective study failed to show reduction in mortality or
progression of disease.17 Randomized controlled trials with large numbers of patients are needed
before IVIG can be recommended as a standard treatment for children with SJS.

References: REFERENCES:
1. von Hebra F. On Diseases of the Skin Including the Exanthemata. Fagge CH, trans. London: New
Sydenham Society; 1866:285-289.
2. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia: report
of two cases in children. Am J Dis Child. 1922;24: 526-533.
3. Lyell A. Toxic epidermal necrolysis. An eruption resembling scalding of the skin. Br J Dermatol.
1956;68:355-361.
4. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal
necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92-96.
5. Schpf E, Sthmer A, Rzany A, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome.
An epidemiologic study from West Germany. Arch Dermatol. 1991;127:839-842.
6. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or
toxic epidermal necrolysis. N Engl J Med. 1995;333: 1600-1607.
7. Prendiville J. Stevens-Johnson syndrome and toxic epidermal necrolysis. Adv Dermatol. 2002;18:
157-173.
8. Mondino BJ, Brown SI, Biglan AW, et al. HLA antigens in Stevens-Johnson syndrome with ocular
involvement. Arch Ophthalmol. 1982;100:1453-1454.
9. Forman R, Koren G, Shear NH. Erythema multiforme, Stevens-Johnson syndrome and toxic
epidermal necrolysis in children: a review of 10 years' experience. Drug Saf. 2002;25:965-972.
10. Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis: clinical findings and prognosis in
87 patients.Arch Dermatol. 1987;123:1160-1165.
11. Garcia-Doval I, LeCleach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens-Johnson
syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol.
2000; 136:323-327.
12. Prendiville JS, Hebert AA, Greenwald MJ, Esterly NB. Management of Stevens-Johnson syndrome
and toxic epidermal necrolysis in children. J Pediatr. 1989;115:881-887.
13. Kim PS, Goldfarb IW, Gaisford JC, et al. Stevens- Johnson syndrome and toxic epidermal
necrolysis: a pathophysiologic review with recommendations for a treatment protocol. J Burn Care
Rehabil. 1983; 4:91-100.
14. Patterson R, Miller M, Kaplan M, et al. Effectiveness of early therapy with corticosteroids in
Stevens- Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann
Allergy. 1994;73:27-34.
15. Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson
syndrome and toxic epidermal necrolysis. Pediatrics. 2003;112:1430-1436.
16. Prins C, Vittorio C, Padilla RS, et al. Effect of high-dose intravenous immunoglobulin therapy in
Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology. 2003;207:96-99.
17. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson

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syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit(ht
on mortality or progression. Arch Dermatol. 2003;139:33-36. tp://www.pediatric
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m)

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[2] http://www.pediatricsconsultantlive.com/bacterial-conjunctivitis
[3] http://www.pediatricsconsultantlive.com/authors/helene-tigchelaar-md
[4] http://www.pediatricsconsultantlive.com/authors/nirupama-kannikeswaran-md
[5] http://www.pediatricsconsultantlive.com/authors/deepak-m-kamat-md-phd

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