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Use of Intravenous Immunoglobulin in Children With Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Seven Cases and Review of the Literature

Denise W. Metry, MD^*,, Peter Jung, MD and Moise L. Levy, MD^*,

^* Departments of Dermatology
Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas

	ABSTRACT

TOP ABSTRACT CASE REPORTS METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis are the most severe cutaneous reactions that occur in children. Off-label use of human intravenous immunoglobulin (IVIG) has been reported in a number of autoimmune and cell-mediated blistering disorders of the skin, including severe cutaneous drug reactions. We review 28 previous reports in which IVIG was used in pediatric patients with SJS and toxic epidermal necrolysis and discuss our experience in 7 children with SJS, in whom no new blisters developed within 24 to 48 hours after IVIG administration and rapid recovery ensued. IVIG seems to be a useful and safe therapy for children with severe cutaneous drug reactions. Well-controlled, prospective, multicenter clinical trials are needed to determine optimal dosing guidelines and to compare the efficacy and safety of IVIG with other potentially effective modalities.

Key Words: Stevens-Johnson syndrome • toxic epidermal necrolysis • intravenous immunoglobulin • IVIG

Abbreviations: SJS, Stevens-Johnson syndrome • TEN, toxic epidermal necrolysis • IVIG, intravenous immunoglobulin

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the most severe cutaneous reactions that occur in pediatrics. Drugs are the predominant inciting agent in both entities. The combined incidence of SJS and TEN is rare, with approximately 1.5 to 2 cases per million per year in the general population.¹ Potential morbidity includes blindness as a result of corneal blistering, internal organ involvement such as pneumonitis or pancreatitis, and joint contractures secondary to scarring (R. A. Krathen, C. A. Woodruff, and M. L. Levy, unpublished data, 2003). Cases of TEN with the most extensive skin detachment are associated with the highest mortality rates, with large case series pointing to an approximate mortality rate of 30% in such instances.^1,2 Sepsis is the principle cause of death.³ Cases of SJS/TEN triggered by long half-life drugs are more likely to result in a fatal outcome.⁴

Supportive therapy is the standard of care for SJS/TEN and includes close monitoring of fluid and electrolyte status, nutritional support, meticulous wound care, and control of pain and infection.² The use of systemic corticosteroids has been widely debated and remains controversial. Although some advocate early, short-term use in drug-induced cases,^5,6 a number of retrospective studies have suggested that systemic corticosteroids not only fail to improve prognosis but also adversely affect outcome by increasing patient susceptibility to sepsis and gastrointestinal tract hemorrhage.^7,8 Despite decades of controversy, the efficacy of systemic corticosteroid use in SJS/TEN has yet to be demonstrated by any controlled clinical trial.

Off-label use of human intravenous immunoglobulin (IVIG) has been reported in a number of autoimmune and cell-mediated blistering disorders of the skin, including SJS/TEN.^9–11 Reports using IVIG in pediatric patients with SJS/TEN are scattered; to our knowledge, a comprehensive review of this modality in children has not been undertaken previously. We thus discuss our experience in 7 children in whom IVIG was used successfully for SJS, and the results of past literature using IVIG for SJS/TEN in pediatric patients.

	CASE REPORTS

TOP ABSTRACT CASE REPORTS METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
A 9-year-old white girl was prescribed oxcarbazepine (Trileptal) for tonic-clonic seizures. Three weeks later, she was admitted to Texas Children’s Hospital with a 4-day history of high fever, dysuria, dysphagia, cough, and photophobia and a 2-day history of a pruritic skin eruption that began on the face and progressed to the upper trunk and extremities. Her medical and medication history was otherwise noncontributory.

Physical examination revealed an acutely ill child, with a temperature of 101°F, pulse of 126, respirations of 24, and blood pressure 101/64. Blanching, erythematous macules were scattered over her upper trunk and extremities and were especially prominent and confluent on the face. A few intact vesico-bullae were also present on her cheeks and upper back. Mucous membrane examination showed bilateral, nonpurulent conjunctivitis; hemorrhagic crusts of the lips; and superficial erosions of the tongue, hard palate, and genital labia. The clinical diagnosis of drug-induced SJS was made, at which time oxcarbazepine was discontinued (Fig 1).

View larger version (86K): [in this window] [in a new window]   Fig 1. Patient 1: Oxcarbazepine-induced SJS, day of admission.

After 2 daily doses of IVIG, the patient was afebrile and her cutaneous disease had stabilized. Existing skin lesions were less inflammatory with healing of previously described vesiculobullae. On the third hospital day, IVIG was withheld, at which time the patient redeveloped fever, general malaise, facial erythema, and new erosions of the oral mucosa. IVIG was resumed that evening for 2 consecutive days with excellent response (Fig 2). Because of the slower healing time of the oral mucosa and her inability to resume oral intake, discharge did not take place until hospital day 10. Three weeks later, she redeveloped mild erythema and tenderness of her oral and vaginal mucosae, which responded to 3 days of oral prednisone (1 mg/kg/day). No additional complications occurred.

View larger version (70K): [in this window] [in a new window]   Fig 2. Patient 1: Clinical improvement (hospital day 5) after 4 doses of IVIG.

	METHODS

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Since August 2000, all patients who were admitted to Texas Children’s Hospital with SJS have been treated with IVIG, 0.3 to 1.0 g/kg/day, based on the protocol published by Viard et al.¹² Six of 7 patients received 4 consecutive daily doses; 1 (patient 6 in Table 1; also described in the aforementioned case report) received doses on days 1, 2, 4, and 5. Administration of IVIG was approved by the Pharmacy and Therapeutics Committee of Texas Children’s Hospital.

	RESULTS

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Table 1 summarizes the results of 7 new and 28 previously published cases of IVIG use in children with SJS/TEN.^13–21 All of our 7 patients had SJS, and the literature contained 12 additional cases of SJS, 11 of TEN and 5 with SJS/TEN overlap. The average patient age in our series was 9.9 years (range: 3–15 years), slightly higher than the past literature with an average age of 8.2 years (range: 22 months to 17 years). There was neither a correlation between age and diagnosis nor a sex predominance in either our or past reports. Drugs were implicated as the inciting agent in approximately two thirds (25 of 35) of cases overall. Anticonvulsants were the trigger in half of drug-induced cases, 5 of which were caused by phenobarbital, 3 by carbamazepine, 1 by oxcarbazepine, 2 by phenytoin, and 1 by lamotrigine. Antibiotics were the second most common drug trigger (9 of 25), 3 of which were caused by penicillin, 2 by sulfa drugs, 2 by cotrimoxazole, 1 by cefuroxime, and 1 by vancomycin. Of the 4 remaining drug-induced cases, 3 were caused by acetaminophen, and in 1 case, the specific drug trigger could not be identified. In one fourth of overall cases (2 of ours and 7 in the past literature), no causative factor could be implicated. One case was attributed to herpes simplex virus.

In our 7 patients, IVIG was initiated an average of 2.7 days after the onset of cutaneous blistering (range: 1–6 days). The average dose of IVIG administered was 2.0 g/kg (range: 1.2–4.0 g/kg). The total dose was distributed evenly over 4 consecutive days (an average daily dose of 0.5 g/kg), with the exception of patient 6, in which dosing occurred on days 1, 2, 4, and 5. A cessation of cutaneous blistering was observed in all patients within an average of 2 days (range: 1–3 days) after IVIG was initiated. We could identify no correlation between the timing or dosing of IVIG and time to objective response. All of our patients survived, and no IVIG-related complications occurred.

Five of our 7 patients (patients 1–5) received systemic corticosteroids. Patient 1 received 60 to 75 mg of prednisone daily for 4 days before IVIG initiation, patient 2 received 40 mg of prednisone daily for 2 days before IVIG, patient 3 received 16 mg/kg IV methylprednisolone 3 days before and 3 days concomitantly with IVIG, patient 4 received 1 dose of IV Solu-Medrol (1 mg/kg) at the time of admission (3 days before IVIG) followed by 3 every-8-hour doses of IV dexamethasone, and patient 5 received 1 dose of IV Solu-Medrol (1 mg/kg) at the time of admission (1 day before IVIG). Patients 6 and 7 had a time to treatment initiation and IVIG dose consistent with the average but did not receive corticosteroids and were observed to have a shorter time to clinical response than patients who had received corticosteroids.

Among published cases, IVIG was initiated an average of 3.75 days after blister onset (range: 1–10 days). The average total dose of IVIG administered was 2.5 g/kg (range: 1.5–5.8 g/kg). Individual data regarding the length of IVIG administration could be ascertained from 20 of 28 cases. Prins et al²⁰ reported 48 cases (8 children, 40 adults) in whom the total dose of IVIG was individually reported, but the period of IVIG administration was reported as an overall mean of 4 days (range: 1–5 days). Of the remaining 20 published cases, an average of 2.2 g/kg (range: 1.5–3.5 g/kg) was administered over an average of 3 days (range: 1–7 days), equivalent to 0.73 g/kg/day for 3 days. The time to objective response could be ascertained in 20 patients. This was not clearly documented in 2 previously reported cases,^15,20 although in 1 of these patients, the skin was noted to be completely healed 8 days after IVIG initiation.¹⁵ In the 6 cases by Morici et al,¹⁶ resolution of fever was noted an average of 2.5 days after IVIG administration, but concomitant skin findings were not documented. Of the remaining 20 published cases, cessation of cutaneous blistering was noted an average of 2.4 days (range: 1–7 days) after IVIG administration. Four patients received systemic corticosteroids before and/or concomitant with IVIG therapy. Similar to our experience, these patients were noted to have a longer time to objective response than patients who had not received corticosteroids. Twelve (25%) of the 48 adult and pediatric patients overall reported by Prins et al²⁰ were noted to have received oral or IV corticosteroids before initiation of IVIG infusion without improvement in symptoms, but individual patient data were not documented. IVIG-related adverse events were reported in 2 patients who experienced a drop in white blood cell count of <2000/µL noted after the second day of IVIG; this normalized by day 5 without clinical consequence. All patients survived.

An attempt was made to evaluate the variables of time to treatment initiation, disease severity, total IVIG dose and duration of treatment, and patient age, relative to time to objective response. Early (within 1–2 days of skin lesion onset; n = 3) time to IVIG initiation correlated with a longer (average: 2.8 days) time to objective response than middle (3–5 days; average time: 2.3 days; n = 10) or late (8–10 days; average time: 1.2 days; n = 7) initiation times. However, early initiation was also associated with lower (2.1 g/kg) total IVIG doses, versus 2.6 g/kg for middle and 3.6 g/kg for late initiation times, which were given over a longer duration. Similarly, looking at the severity of diagnosis variable revealed SJS (n = 5) versus TEN (n = 8) cases to be associated with shorter times to treatment initiation (1.2 days vs 3.8 days), lower IVIG dose (1.7 g/kg vs 2.7 g/kg total), and longer times to objective response (3.2 vs 2.4 days). It is interesting that cases of SJS-TEN overlap (n = 6) were associated with even longer times to treatment initiation (4.5 days), higher total IVIG doses (3.2 g/kg), and shorter times to objective response (1.8 days) than patients with TEN. There seemed to be no correlation between patient age or cause (especially drugs with longer vs shorter half-lives) and any other variable.

	DISCUSSION

TOP ABSTRACT CASE REPORTS METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
SJS and TEN are severe cutaneous reactions that carry significant morbidity and mortality risks for children who are affected. There is much overlap between these 2 conditions, which are likely part of the same disease spectrum. Both are most commonly precipitated by drugs and generally begin with a prodrome of high fever, sore throat, and malaise, followed by the rapid onset of cutaneous blistering. The epidermal detachment that occurs in SJS/TEN is preceded by immune-mediated keratinocyte apoptosis, or programmed cell death, although the apoptosis that occurs in SJS is generally more focal.²² Both SJS and TEN are characterized by epidermal detachment in addition to mucosal involvement, although the development of large sheets of epidermal detachment in the absence of mucosal involvement is more characteristic of TEN.²³ The frequent presence of overlapping clinical features in a given patient often makes definitive classification difficult. According to a consensus definition for the classification of SJS and TEN, a patient with total body surface area epidermal detachment of 10% are classified as SJS, >30% as TEN, and between 10% and 30% as SJS-TEN overlap.²⁴

Given the importance of immune mechanisms in inflammatory drug reactions, IVIG has emerged as a potential immunomodulatory therapy for SJS/TEN. Although well-controlled trials have yet to be designed, results from the small number of patients treated thus far seem favorable. In 1992, Amato et al¹³ reported the first case of IVIG use in a 5-year-old girl with SJS. Subsequently, a landmark study by Viard et al¹² demonstrated the pathogenesis of IVIG in TEN. Through a series of in vitro experiments, the authors showed that a drug trigger could activate keratinocyte production of an apoptotic ligand, known as the CD95 (fas) ligand. The binding of this ligand to a CD95 (fas) apoptotic receptor located on the keratinocyte cell surface led to programmed cell death. IVIG demonstrated the capacity to block the apoptotic ligand from binding to this receptor, thus preventing keratinocyte apoptosis and subsequent epidermal detachment (Fig 3). The authors then applied their in vitro data to human subjects. In an open, uncontrolled study, IVIG was administered to 10 adult patients with drug-induced TEN. The dosage regimen used, 0.4 to 0.75 g/kg/day for 4 consecutive days, was based on IVIG treatment recommendations for immune thrombocytopenic purpura. Although the details of this study are limited, the authors noted an interruption of cutaneous blistering and signs of wound healing, which occurred in all patients within 24 to 48 hours after IVIG administration.¹²

View larger version (40K): [in this window] [in a new window]   Fig 3. Pathogenesis of IVIG in SJS/TEN.

The immunomodulatory effects of IVIG are complex, involving modulation of the expression and function of reticuloendothelial Fc receptors; interference with the activation of complement and cytokine networks; provision of anti-idiotype antibodies; and effects on the activation, differentiation, and effector functions of T and B cells. Therefore, in addition to its ability to block keratinocyte-mediated apoptosis, IVIG may have additional effects that contribute to its overall therapeutic benefit in patients with severe cutaneous drug reactions.^25,26 For example, patients with severe cutaneous drug reactions are prone to infectious complications that IVIG may limit through its anti-infectious properties. Furthermore, IVIG restores protein and fluid, which may help to limit the extent of fluid loss that occurs through the denuded skin.^20,27

Given the multiple variables, differences in treatment protocols, and subjective evaluation of clinical response, it was challenging to compare our results with those of past series. Several variables, such as the presence or absence of concomitant disease, length of fever, duration of hospitalization, extent of body surface area involved, and laboratory parameters, were not available in enough patients to reach significant conclusions. Neither were we able to establish retrospectively a reliable control group. However, we did observe the interruption in cutaneous disease progression noted by previous authors within 24 to 48 hours after IVIG administration. We have also observed a lessening of the degree of cutaneous erythema that occurs, at which time blisters, which had already developed or were in the process of developing at the time of IVIG administration, heal with superficial desquamation and postinflammatory hyperpigmentation (Fig 2). Also to be noted is that the results of length of time to objective response reported in our and previous publications were likely longer than actual, because response was recorded as days rather than as hours; for example, a response seen within 24 to 48 hours would be documented as a response seen at 2 days.

Recently, Viard and co-authors published a multicenter, retrospective analysis of 48 adult and pediatric TEN patients who were treated with IVIG and concluded this modality to be safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. On the basis of their experience, early treatment with IVIG at 1 g/kg/day for 3 consecutive days was recommended.²⁰ Our results support these recommendations, with the best response seen with IVIG doses of 0.5 to 1.0 g/kg administered over 3 to 4 days, resulting in a time to objective response seen within an average of 2 to 3 days after IVIG initiation. According to our results, a higher IVIG dose (between 0.5 and 1.0 g/kg/day) was more relevant in achieving a faster treatment response than length of time to treatment initiation or disease severity. Duration of therapy <3 days does not seem to be as effective as 3 or 4 consecutive days. This was supported by our experience, including patient 6 (case report), who experienced a relapse on day 3 when IVIG was held but then responded readily when therapy was resumed. Consecutive therapy seems to be needed despite the 3-week half-life of IVIG, likely because of the rapid binding immediately necessary to achieve disease control.

Although relapses immediately after IVIG discontinuation have not been reported, 2 of our patients experienced late disease reactivation after IVIG completion and clinical improvement. This phenomenon has also been described in SJS/TEN treated with systemic corticosteroids and cyclosporine⁸ but not, to our knowledge, with IVIG. The first occurred in patient 6 (case report), who experienced a minor disease reactivation 3 weeks after therapy, which responded readily to short-course prednisone. The second occurred in a 3-year-old black boy with SJS secondary to vancomycin (patient 5). On day 10 of hospitalization, 5 days after his last IVIG infusion, he developed new blisters over his lower extremities in association with fever and malaise (Fig 4). A fifth dose of IVIG was administered, and within 24 hours, he was afebrile with no new blisters and evidence of cutaneous healing (Fig 5). No additional complications occurred. Notably, SJS in both patients was triggered by relatively long half-life drugs. Appropriate management of disease reactivation has yet to be determined.

View larger version (68K): [in this window] [in a new window]   Fig 4. Patient 2: Post-IVIG disease reactivation in vancomycin-induced SJS.

View larger version (101K): [in this window] [in a new window]   Fig 5. Patient 2: Evidence of cutaneous healing 24 hours after the fifth IVIG dose.

Side effects from IVIG occur in <5% of cases and are generally mild and self-limited.²⁸ All of our patients tolerated IVIG without difficulty, whereas only 2 in past reports experienced a minor drop in white blood cell count that quickly resolved without clinical significance. The major factors limiting widespread use of IVIG for SJS/TEN and related disorders are availability and cost. Manufacturer costs range from $58.00 to $119.00 per gram. Thus, the average cost of a 20-kg child to receive an IVIG dose of 1.0 g/kg/day for 3 consecutive days is approximately $3500 US at the $58.00/g minimum (Texas Children’s Hospital Pharmacy Data, 2002). However, such costs certainly outweigh the potential financial and emotional costs related to prolonged hospitalization and secondary morbidity.

	CONCLUSIONS

TOP ABSTRACT CASE REPORTS METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
IVIG seems to be a useful and safe therapy for children with SJS/TEN. IVIG doses of 0.5 to 1.0 g/kg administered over 3 days are most effective, but in children on longer half-life drugs, mild relapses may be seen after IVIG discontinuation, despite clinical improvement. Well-controlled, prospective, multicenter clinical trials are needed to determine optimal dosing guidelines and to compare the efficacy and safety of IVIG with other potentially effective modalities.

	FOOTNOTES

 
Received for publication Jul 12, 2002; Accepted Apr 4, 2003.

Reprint requests to (D.W.M.) Departments of Dermatology and Pediatrics, Dermatology Clinic, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin St, CC 620.16, Houston, TX 77030-2399. E-mail: dmetry{at}bcm.tmc.edu

	REFERENCES

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