Stevens-Johnson syndrome and toxic epidermal necrolysis in Asian children

Article Outline

• Abstract
• Methods
• Results
  • Patient characteristics
  • Causes
  • Clinical presentation
  • Laboratory investigations
  • Treatment and outcome
• Discussion
• References
• Copyright

Background

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe drug reactions. There have been few reviews of SJS and TEN in children.

Objectives

To evaluate the clinical profile and treatment outcomes of 15 pediatric patients with SJS or TEN.

Methods

We retrospectively reviewed the case notes of all patients diagnosed with SJS or TEN admitted to a tertiary care pediatric hospital from 2001 to 2006.

Results

We identified 13 cases of SJS, 1 case of SJS/TEN overlap and 1 case of TEN. Four patients were treated with intravenous immunoglobulin (IVIg), 5 patients were treated with systemic corticosteroids, and 6 patients were treated with supportive therapy only. The time to cessation of progression of disease was not significantly different in these 3 groups of patients. The duration of hospital stay was longer for patients treated with IVIG compared with those treated with systemic corticosteroids or supportive therapy. The only death was the patient with TEN treated with IVIG.

Limitations

This was a retrospective study with a very small number of patients.

Conclusion

The use of intravenous immunoglobulins or systemic corticosteroids did not improve the outcome of SJS and TEN.

Key words: corticosteroids, intravenous immunoglobulins, Stevens-Johnson syndrome, toxic epidermal necrolysis

Abbreviations used: ALT, alanine transferase, BSA, body surface area, CRP, C-reactive protein, ESR, erythrocyte sedimentation rate, IVIG, intravenous immunoglobulin, SJS, Stevens-Johnson syndrome, TEN, toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), conditions characterized by extensive epidermal cell death, are among the most severe mucocutaneous reactions. They are considered variants of the same disorder with epidermal detachment of less than 10% of total body surface area (BSA) classified as SJS, more than 30% detachment as TEN, and between 10% and 30% as transitional/overlap SJS/TEN.¹

Although SJS may be caused by drugs or infectious agents (eg, Mycoplasma pneumoniae),² TEN is almost exclusively attributed to drugs. More than 200 medications have been implicated, most commonly anticonvulsants, sulfonamide antibiotics, penicillins, allopurinol, and oxicam nonsteroidal anti-inflammatory drugs.³, ⁴, ⁵ Mortality rates of approximately 5% are reported in SJS, with TEN fatal in up to 30% of cases.⁶ Mortality rates in children have been much lower.⁷, ⁸, ⁹ A validated composite score (SCORTEN) has been used to predict mortality in patients with SJS/TEN.¹⁰, ¹¹

Treatment of SJS and TEN includes the prompt discontinuation of any inciting drug and good supportive care. The use of systemic corticosteroids in TEN remains controversial and associated with complications such as sepsis and gastrointestinal hemorrhage. However, high-dose systemic corticosteroid therapy (eg, dexamethasone pulse therapy) may play a role in the treatment of early TEN before widespread skin loss occurs.¹² A role for systemic corticosteroid therapy in SJS is less controversial with several papers recommending its use to reduce morbidity and improve patient outcome.¹³, ¹⁴ Treatment of SJS and TEN with intravenous immunoglobulin (IVIG) has been reported in several case series, but with conflicting results. There are only a few reports of its use in pediatric patients.⁹, ¹⁵, ¹⁶, ¹⁷

We undertook a retrospective analysis of patients with SJS and TEN admitted to the Department of Paediatric Medicine, Kandang Kerbau Hospital, a tertiary care pediatric referral centre in Singapore, over a 5-year period, and report the clinical findings, investigations, treatment, and outcome in these patients.

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Methods 

This retrospective study was approved by the Institutional Review Board Committee of Kandang Kerbau Women's and Children's Hospital. Patients admitted between January 2001 and December 2006, with a diagnosis of SJS, SJS/TEN overlap, or TEN, were identified from the hospital's computer database. A diagnosis of SJS was based on the finding of two or more mucosal sites of involvement, with or without skin involvement and epidermal sloughing involving less than 10% BSA. A diagnosis of TEN and SJS/TEN overlap was based on the presence of epidermal sloughing involving more than 30% and between 10% and 30% BSA, respectively. We reviewed the case notes, charts, investigation results, and treatment records of these patients. Epidemiological data obtained included the age, gender, ethnic group, and medical history. Clinical information obtained included presenting complaints, inciting drug(s), and the duration between the initial consumption of the drug and the onset of symptoms. Investigation results included complete blood cell count, renal panel, liver enzymes, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, bacteriological cultures, Mycoplasma serology by enzyme-linked immunosorbent essay, viral isolation and histopathology of skin punch biopsy specimens. Treatment regimens, duration of stay in the intensive care unit, duration of hospitalization, complications and mortality were also recorded. Significance tests to compare the results of treatment regimens were performed by means of Student t tests.

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Results 

Patient characteristics 

We identified 15 patients. Table I summarizes patients' characteristics, causes, treatment regimens, complications, and outcomes of these patients. Patients were 3 to 14 years of age, with a mean of 9 years. There was a predominance of male patients, with 11 boys and 4 girls. There were 9 Chinese patients, 5 Malay patients, and 1 Indian patient. Thirteen had a diagnosis of SJS, 1 patient had a diagnosis of SJS/TEN, and 1 patient was diagnosed with TEN.

Table I. Characteristics of patients admitted for SJS or TEN

d, Day(s); GE, gastroenteritis; IV, intravenous; IVIG, intravenous immunoglobulin; MOF, multiple organ failure; NA, not available; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; UTI, urinary tract infection.

Causes 

Drugs were the most common cause of SJS (11 of 15 patients). Three patients had confirmed Mycoplasma infection. No cause was ascertained in one patient with SJS. The most common drugs implicated were anticonvulsants and the beta-lactam antibiotics. Three patients reacted to carbamazepine, one patient each to valproate and lamotrigine, two patients to amoxicillin, one to amoxicillin/clavulanate, one to cloxacillin, one to penicillin, and one to trimethoprim/sulfamethoxazole (cotrimoxazole). The mean number of days between ingestion of the drug and onset of symptoms was 9 days, with a range of 2 to 18 days. Patients who had earlier onset (2-3 days) of symptoms gave a history of ingestion of the same drug. Conversely, patients who had a later onset of symptoms (10-18 days) were prescribed the drug for the first time.

Clinical presentation 

Except for one child who presented with mucosal lesions only, the patients had both mucous membrane and cutaneous involvement. The most common skin manifestations were an exanthematous eruption (7 patients) and atypical target lesions (7 patients). Six patients developed blisters and bullae with erosions, and 3 patients had purpuric lesions. All patients had at least two mucosal surface sites of involvement, with oral mucosal involvement in 15, eye involvement in 11, and genital lesions in 10 patients. Fever higher than 38°C was seen in 12 of the 15 patients, and 5 had upper respiratory tract symptoms (eg, cough and blocked nose).

Laboratory investigations 

The mean white blood cell count was 10.76 × 10⁹/L (range 2.91-17.6 × 10⁹/L), mean hemoglobin level was 13.4 g/dL (range 10.7-16.7 g/dL) and mean platelet count was 242 × 10⁹/L (normal: 150-400 × 10⁹/L). Only the patient with TEN had abnormal white blood cell count (2.9 × 10⁹/L), hemoglobin (10.7 g/dL), and platelet (63 × 10⁹/L) levels on admission. CRP levels ranged from 5.0 to 131.5 mg/L with a mean of 50.3 mg/L (normal: 1-10 mg/L). ESR ranged from 8 to 130 mm/h, with a mean of 46.2 mm/h (normal: 0-10 mm/h). CRP levels and ESR were normal in the two patients with SJS/TEN overlap and TEN.

Liver enzymes were overtly abnormal in two patients. Patient 14, with SJS caused by lamotrigine, had increased serum alanine transaminase (ALT), 247 U/L (normal: 7-31 U/L), and aspartate transaminase, 560 U/L (normal: 16-54 U/L) levels. The patient with TEN (patient 15), who succumbed to multi-organ failure, had increased serum ALT 270 U/L, aspartate transaminase 418 U/L, alkaline phosphatase 858 U/L (normal: 110-374 U/L), and total bilirubin 166 μmol/L (normal: 2-18 μmol/L) levels. Three other patients had marginally raised serum ALT levels of 36-62 U/L. Except for the patient with TEN, all patients had normal renal function.

Three patients had positive mycoplasma serology. Herpes simplex virus isolation from mouth erosions was negative in 9 patients tested. Other viral studies (EBV serology, immunofluorescence for respiratory viruses) performed in a small number of patients were negative. Three patients had a skin biopsy performed to confirm the diagnosis. All 3 biopsy specimens showed an interface dermatitis with apoptotic bodies in the epidermis and a superficial perivascular infiltrate of mononuclear cells with some polymorphonuclear leukocytes.

Treatment and outcome 

Decisions on treatment were based on the severity of disease, as well as on the preference of the treating physician. Three patients with SJS and the only patient with TEN were treated with IVIG, 2 g/kg, administered in divided doses over 2 or 4 days. The patients with SJS were started on a regimen of IVIG 6 to 7 days after onset of the rash. The average time to cessation of progression of disease, defined as cessation of progression of rash and blistering, was 2.7 days (range: 2-3 days). The patient with TEN received IVIG 34 days after the onset of skin disease. This patient was transferred to our institution after 2 weeks of inpatient treatment at a hospital in a neighboring country and died as a result of multiple-organ failure and neutropenic sepsis.

Five patients with SJS received systemic corticosteroids. Three patients received oral prednisolone 0.5-1.5 mg/kg per day for a period of 5 days to a month (with tapering doses). Two patients were commenced on a regimen of intravenous hydrocortisone, 10-15 mg/kg per day, with subsequent conversion to oral prednisolone. These patients were started on a regimen of systemic corticosteroids for an average of 4 days (range: 2-6 days) after onset of the rash. Three also received a macrolide antibiotic (two receiving clarithromycin, one azithromycin) for treatment of mycoplasma infection. The average time to cessation of progression of disease in this group was 1.5 days (range: 1-2 days).

The remaining 6 patients received supportive therapy only. From the time the inciting medication was stopped to cessation of progression of disease in this group was 4.2 days (range: 2-6 days). The time to cessation of progression of disease in all 3 groups was not significantly different (P > .05).

Apart from the patient who died, complications were few and minor. Two patients had mild hypotension that responded to intravenous fluid therapy, one patient had hyponatremia, and one patient developed cellulitis at the intravenous site. One patient (patient 11) developed corneal ulceration a few days after diagnosis of SJS. However, this resolved after 3 weeks of topical antibiotic eye-drops.

The average length of hospital stay for the IVIG-treated group was 23 days (range: 13-45 days), the systemic corticosteroid-treated group 6.8 days (range: 3-9 days) and the supportive therapy group 6.3 days (range: 3-9 days).

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Discussion 

The incidence of SJS and TEN is low, with an estimate of between 1.5 to 2 cases per million per year in the general population, and 0.07 to 0.2 per 1000 hospitalized patients.⁶, ¹⁸, ¹⁹ In our series, there were 15 cases of SJS and TEN over a 5-year period, giving an estimated incidence of about 2 to 2.5 cases per million per year in the pediatric population. Similar to previous reports, the incidence of SJS far exceeds that of TEN. Contrary to reports of a higher incidence in women,² our series had more boys than girls with a ratio of about 2.5:1. The most common drugs implicated were the anticonvulsants and beta-lactam antibiotics. There was only one case of sulfonamide causation probably because this class of drug is now uncommonly used as first-line antibiotic therapy for children in our country. Mycoplasma infection was a cause of SJS in 3 children. This association appears to be more common in the pediatric population compared to adult patients.²

All our patients were of Asian descent, with the majority being Chinese. It has been shown that genetic susceptibility plays a strong role in the pathogenesis of SJS and TEN. A recent study showed that HLA-B∗1502 is strongly associated with carbamazepine-induced SJS in a Han Chinese population.²⁰ Another study showed a strong association for HLA-B∗5801 with allopurinol-induced SJS/TEN in the Japanese population.²¹ In the future, the understanding of HLA associations with drug reactions may be useful to predict a patient's susceptibility to a medication before treatment with the drug is instituted. The US Food and Drug Administration has recommended genotyping all Asian patients for HLA-B∗1502 before commencing treatment with carbamazepine.²²

SCORTEN, a TEN-specific severity of illness score was first proposed by Bastuji-Garin et al¹⁰ in 2000; it is based on 7 prognostic factors of age, malignancy, surface area involved, heart rate, serum urea, bicarbonate, and glucose. When calculated within 24 hours after admission, SCORTEN has been shown to accurately predict the risk of mortality. As its use in the pediatric population had not been fully validated, it was not used in our center during the period of our study.

Treatment of SJS and TEN requires prompt diagnosis with immediate cessation of the causative drug. It has been shown that the earlier the causative drug is withdrawn, the better the prognosis.²³ Optimal supportive therapy is still of utmost importance in the treatment of patients with SJS and TEN. Patients should ideally be managed in a specialized intensive care or burns unit. Essential aspects of supportive therapy include maintenance of fluid and electrolyte homeostasis; environmental temperature control; prevention and treatment of infections; respiratory and nutritional support, and adequate analgesia. Energy requirements of pediatric patients with SJS and TEN are increased, and the application of a 30% factor to resting energy requirements should be made when calculating nutritional support.²⁴ Early ophthalmologic consultation is essential in evaluating eye involvement and preventing ocular complications.²⁵

Because of the low incidence of the disease, randomized controlled trials comparing immunosuppressive therapies for SJS and TEN are rare. There has been only one prospective, randomized-controlled trial in the treatment of TEN, involving the use of thalidomide, which was terminated early because of an increased mortality rate in the treatment arm. The majority of reports in the literature involve single-case observations, case series, or small, uncontrolled studies. The largest series to date, arising from the EuroSCAR study, involved a retrospective analysis of 281 patients from France and Germany. This study compared the use of supportive therapy, IVIG, corticosteroids, and IVIG plus corticosteroids. The authors observed no significant benefit from treatment and concluded that evidence is insufficient to recommend any specific treatment.²⁶

In our study, 4 patients were treated with IVIG (total dose 2 g/kg), 5 patients were treated with systemic corticosteroids (IV hydrocortisone or oral prednisolone) and 6 patients were treated with supportive therapy only. There was no significant difference in the time to cessation of disease between the 3 groups of patients. The duration of hospital stay for the IVIG group was longer than the other two groups of patients. However, we cannot exclude bias toward administering IVIG for more severely affected patients.

In 1998, Viard et al²⁷ first reported that the interaction between Fas and FasL might play a role in apoptosis in TEN and showed that IVIG inhibited Fas-mediated apoptosis in sensitive cell lines by blocking Fas receptors. This article also showed a positive outcome in a series of 10 patients with SJS or TEN treated with IVIG. Since then, there have been several studies evaluating its use in SJS and TEN. Most of these studies have shown a trend toward improved mortality,²⁸, ²⁹ whereas 4 studies did not show any benefit on mortality rates.²⁶, ³⁰, ³¹, ³² Patients who received IVIG within the first 4 days of onset of the skin eruption appeared to have a shorter time to cessation of disease progression and complete re-epithelialization. Total doses of 3 to 4 g/kg appeared to be more effective than doses of 2 g/kg.

Studies documenting the use of IVIG in children with SJS and TEN appear to show a favorable outcome. However, this may be due to the disease being relatively milder in children compared to adults. Table II summarizes these articles.

Table II. Studies of SJS/TEN in pediatric patients

pts, Patients; for other abbreviations, see legend for Table I.

The outcome of pediatric patients treated with systemic corticosteroids is also unclear. Léauté-Labrèze et al⁸ treated 10 children with SJS with prednisolone, 1 mg/kg per day for 1 week, but found that the mean duration of disease was similar to patients in the non-steroid group. Forman, Koren, and Shear⁷ described 11 children with SJS or TEN who survived after treatment with oral corticosteroids, but there was no mention of dosage or duration of steroid used. Lam et al³³ treated 10 cases of SJS or TEN with 1 to 2 mg/kg per day of prednisolone for 3 to 5 days. Those patients with poor responsiveness to steroids were treated with additional IVIG at 1 mg/kg per day with satisfactory results. More recently, the use of cyclosporine, 3 mg/kg per day, has been reported in a small case series and several case reports.³⁴ In addition to its anti-apoptotic activity, cyclosporine inhibits CD8 activation, leading to inhibition of cytotoxic activity. None of our patients was treated with cyclosporine.

In conclusion, early withdrawal of a causative drug and optimal supportive therapy are still the most important aspects of management of SJS and TEN. In our pediatric patients, treatment with IVIG or systemic corticosteroids did not appear to improve the outcome of the disease. With a better understanding of the pathogenesis of the condition, more specific therapies may emerge that can target specific mediators of apoptosis.

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