A Girl With Widespread Blistering, Scabbing, and Swelling

A 6-year-old girl presented with a 3-day history of a widespread bullous, erythematous, pruritic eruption, bilateral eye irritation, swollen lips, and sores in her mouth.

Ten days ago, she had a fever, malaise, myalgia, and a sore throat. She was seen by her family physician and was started on oral cefprozil.

Physical examination revealed a widespread maculopapular rash, scabs, and multiple bullae on an erythematous base on her body and extremities. She also had swollen lips, erosions on the tongue and hard palate, an inflamed pharynx, tonsillar exudates, injected conjunctiva, and several enlarged cervical lymph nodes.

What’s your diagnosis?

(Answer and discussion on next page)

Answer: Stevens-Johnson syndrome

In 1922, Stevens and Johnson described 2 children who had developed an acute mucocutaneous syndrome characterized by extensive mucosal necrosis and purpuric macules on the skin, associated with fever, ophthalmia, and stomatitis, with a probable infectious origin.¹ The syndrome now bears their names. Stevens-Johnson syndrome is a potentially life-threatening disease characterized by a sudden onset of cutaneous erythema and inflammatory bullous lesions on the skin, with epidermal detachment involving less than 10% of the total body surface area, accompanied by involvement of 2 or more mucosal surfaces.² According to a consensus classification, patients with epidermal detachment of greater than 30% of body surface area are classified as having toxic epidermal necrolysis, whereas those with between 10% and 30% are classified as having Stevens-Johnson syndrome–toxic epidermal necrolysis overlap.^2,3

Incidence

The incidence is approximately 1 to 6 cases per million persons per year.² The incidence increases with age, probably due to increases in drug prescriptions and comorbidities that modify drug effects.⁴ Boys and girls are equally affected.^2,4

Etiology and Pathogenesis

Most cases are clearly linked to medications such as sulfonamides, penicillins, cephalosporins, quinolones, anticonvulsants, and nonsteroidal anti-inflammatory drugs.^4-6 Other causes include infectious agents (eg, Mycoplasma pneumoniae, Yersinia enterocolitica, Mycobacterium tuberculosis, group A streptococci, herpes simplex virus, human immunodeficiency virus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, cytomegalovirus, dengue virus), vaccination (eg, measles, mumps, and rubella vaccine; Haemophilus influenzae vaccine), systemic diseases (eg, malignancy, immunodeficiency, systemic lupus erythematosus), physical agents (eg, contrast medium, radiation exposure), and food.^4,6-8

Stevens-Johnson syndrome represents a severe hypersensitivity reaction (type 4 reaction) to a variety of agents against keratinocytes. Activated CD8⁺ cytotoxic T lymphocytes, along with natural killer (NK) cells and macrophages, are the main triggers of mucocutaneous damage.^3,6 These triggers could activate CD95 ligand (FasL). Binding of this ligand to a CD95 (Fas) apoptotic receptor located on the surface of keratinocytes activates caspase 8, which results in nuclease activation.^9,10 This in turn will lead to keratinocyte apoptosis and cause separation of the epidermis from dermis.^4,7 Activated T lymphocytes and NK cells also could lead to massive necrolysis by secreting perforin, granzyme B, granulysin, and cytokines such as interleukin-6 and tumor necrosis factor α.⁴

There is a genetic predisposition to drug hypersensitivity reactions. Individuals with antigens HLA-B*1502, HLA-B*5701, HLA-B*5801, HLA-Bw44, and HLA-DQB1*0601, along with those who have a decreased capacity to detoxify reactive intermediate drug metabolites, are more susceptible to developing Stevens-Johnson syndrome.^4,6,11,12

Histopathology

Histopathologic examination of a classic lesion shows epidermal necrosis of keratinocytes and vacuolar change along the epidermal basal layer with adjacent subepidermal vesicle or blister.² Perivascular lymphocytic infiltrate occurs mainly in the dermal-epidermal junction.¹⁰ T lymphocytes in the dermis are predominantly CD4⁺, while those in the epidermis are CD8⁺.¹⁰

Clinical Manifestations

The typical interval between onset of drug therapy and Stevens-Johnson syndrome is between 1 and 2 weeks.⁶ The prodromal period is 1 to 14 days. During the prodromal period, affected patients may have fever, malaise, headache, myalgia, and arthralgia.²

Typically, skin lesions are symmetrical and consist initially of erythematous macules with purpuric centers (targetoid lesions) on the face, trunk, and extensor surfaces of the extremities.⁵ These macules rapidly develop central necrosis to form vesicles, bullae, and areas of denudation. New lesions appear in crops. The affected skin is tender.⁵

In response to gentle shear pressure, the affected skin becomes wrinkled and peels off like wet tissue paper (Nikolsky sign).⁴ The oral mucosa almost always is affected. Sore throat and a burning sensation and erythema of the lips often are the presenting signs, followed by the development of bullae, ulceration, and hemorrhagic crusting of the lips.⁵ Ocular involvement occurs in approximately 70% of patients and consists of eyelid edema, purulent conjunctivitis, conjunctival membrane or pseudomembrane formation, corneal ulceration, keratitis, anterior uveitis, and panophthalmitis.^5,12 Mucosal involvement also may occur on the anogenital, esophageal, gastrointestinal, and tracheobronchial mucosa.⁹ Lymphadenopathy frequently is present, and hepatosplenomegaly may occur.

Diagnosis

The diagnosis is mainly clinical. Nonspecific laboratory abnormalities include leukocytosis, eosinophilia, proteinuria, hematuria, elevated erythrocyte sedimentation rate, and elevated C-reactive protein. Neutropenia is an indicator for a poor prognosis.¹¹ If an infectious cause is suspected, appropriate culture, serology tests, and polymerase chain reaction testing (to assess viral replication) should be done.⁴ Skin biopsy may be necessary if the diagnosis is in doubt.

Stevens-Johnson syndrome should be differentiated from Stevens-Johnson syndrome–toxic epidermal necrolysis overlap, toxic epidermal necrosis, and erythema multiforme. The former 2 conditions can be distinguished by the extent of the epidermal detachment (see above). Erythema multiforme is characterized by acrally distributed, distinct targetoid lesions, sometimes with mucosal erosions. It does not, however, have as prominent mucosal involvement or widespread erosions compared with Stevens-Johnson syndrome.⁹

Other differential diagnoses include erythematous drug reaction, pustular drug eruption, exfoliative erythroderma, toxic shock syndrome, staphylococcal scalded skin syndrome, linear immunoglobulin A dermatosis, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, Kawasaki disease, herpangina, and Behçet syndrome. In case of doubt, a skin biopsy can be performed, which typically shows necrosis of the lower epidermal cells and interface dermatitis.

Complications

Complications include sepsis, dehydration, electrolyte imbalance, pneumonia, bronchiolitis obliterans, myocarditis, hepatitis, liver cirrhosis, pancreatitis, enterocolitis, cutaneous dyschromia, cutaneous scarring, nail dystrophy, dry eyes, trichiasis, symblepharon, distichiasis, ocular scarring, xerostomia, joint contractures, and strictures of the urethra, anus, vagina, and esophagus.^12,13 Approximately 47% of affected children experience long-term complications.¹⁴

Prognosis and Management

The mortality is about 1% to 5% for Stevens-Johnson syndrome.¹² The recurrence rate is approximately 18%, which suggests vulnerability and potential genetic predisposition.¹⁴

The patient should be admitted to a pediatric intensive care unit if possible.¹⁵ Low mortality can be ensured with optimal pediatric intensive care unit care.¹⁶

Treatment is mainly symptomatic and supportive. If an offending drug is suspected, it should be discontinued as soon as possible. Careful attention to fluid and electrolyte balance; nutritional support; meticulous skin, mouth, and eye care; pain control; and treatment of secondary bacterial infection are the mainstays of care.⁵ Prophylactic antibiotics in the absence of an infection, however, are not indicated.¹⁰

Intravenous immunoglobulin 2 to 4 g/kg/day for 3 to 4 days, given within 4 days of the eruption of the skin lesions, has been shown to be an effective treatment.⁴ It is suggested that intravenous immunoglobulin works by inhibiting Fas and Fas ligand, thereby preventing apoptosis of keratinocytes.⁴ There is conflicting evidence for a small benefit from systemic corticosteroids, with equivocal evidence suggesting a risk of harm.¹⁷ As such, systemic corticosteroids cannot be recommended in the routine management of children with Stevens-Johnson syndrome.¹⁷

Alexander K. C. Leung, MD—Series Editor, is a clinical professor of pediatrics at the University of Calgary and a pediatric consultant at the Alberta Children’s Hospital in Calgary.

Benjamin Barankin, MD, is medical director and founder of the Toronto Dermatology Centre.

Kam-Lun Ellis Hon, MD, is a professor of pediatrics at the Chinese University of Hong Kong.

References

1. 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(6):526-533.

2. Powers S, Carter-Beard G. Rash, eye pain, lesions in an adolescent. Pediatr Rev. 2010;31(12):e86-e90.

3. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803-813.

4. Ferrandiz-Pulido C, Garcia-Patos V. A review of causes of Stevens–Johnson syndrome and toxic epidermal necrolysis in children. Arch Dis Child. 2013;98(12):988-1003.

5. Leung AKC, Hon K-LE. Stevens-Johnson syndrome. In: Lang F, ed. Encyclopedia of Molecular Mechanisms of Disease. Berlin, Germany: Springer-Verlag; 2009:1992-1993.

6. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part 1. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69(2):
173.e1-173.e13.

7. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Crit Care Med. 2011;39(6):1521-1532.

8. Manwani NS, Balasubramanian S, Dhanalakshmi K, Sumanth A. Stevens Johnson syndrome in association with Mycoplasma pneumonia. Indian J Pediatr. 2012;79(8):1097-1099.

9. Treat J. Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatr Ann. 2010;39(10):667-674.

10. Worswick S, Cotliar J. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of treatment options. Dermatol Ther. 2011;24(2):207-218.

11. Cairns B, Rich M. Fever, rash, and peeling skin. J Fam Pract. 2011; 60(1):9-12.

12. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;5:39.

13. Nam Y-H, Lee S-W, Lee S-K, et al. Liver cirrhosis as a delayed complication of Stevens-Johnson syndrome. Intern Med. 2011;50(16):1761-1763.

14. Finkelstein Y, Soon GS, Acuna P, et al. Recurrence and outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Pediatrics. 2011;128(4):723-728.

15. Prashanth GP, Pai VV. A retrospective cohort study of dermatological problems observed in paediatric intensive care unit. J Eur Acad Dermatol Venereol. 2012;26(9):1105-1108.

16. 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(6):e351-e358.

17. Corrick F, Anand G. Question 2: would systemic steroids be useful in the management of Stevens-Johnson syndrome? Arch Dis Child. 2013; 98(10):828-830.