Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children

Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children Payam Tristani-Firouzi, MD,a Marta J. Petersen,a Jeffrey R. Saffle, MD,b Stephen E. Morris, MD,b and John J. Zone, MDa Salt Lake City, Utah Background: Toxic epidermal necrolysis (TEN) is an acute illness characterized by rapid onset of skin necrosis and high mortality. Standard treatment is primarily aimed at supportive care in a burn unit setting. Objective: We evaluated the outcome of 8 pediatric patients treated for TEN with intravenous immunoglobulin (IVIg) over a 3-year period. Methods: We performed a retrospective analysis of pediatric patients with a diagnosis of TEN between 1999 and 2001, obtained from a computerized database. Results: Mean body surface involvement of 8 patients treated with IVIg was 67%. The average length of hospitalization was 13.6 days, with an average delay in treatment of 3.2 days. The average time to arrest in progression of lesions was 2.1 days and to complete re-epithelialization, 8.1 days. The mortality rate was 0%. The majority of complications were infectious. Conclusion: IVIg is a safe and effective treatment for TEN in the pediatric population. Randomized trials are needed to further evaluate the efficacy of IVIg compared with other modalities. (J Am Acad Dermatol 2002;47:548-52.)

T

oxic epidermal necrolysis (TEN) is a rare, acute, life-threatening illness, which is characterized by sudden onset of widespread necrosis resulting in sloughing of the epidermis and frequent mucous membrane involvement. TEN represents an extreme form of an adverse drug reaction, most commonly to sulfonamides, antiepileptic drugs (phenytoin, phenobarbital), and penicillin derivatives.1 Some authors consider TEN to represent an extreme form of Stevens-Johnson syndrome with ⱖ30% body surface involvement.2 TEN occurs in all age groups, including newborns, infants, and children, but is more prevalent in the elderly possibly because of greater medication intake. It is currently widely accepted that the intensive care unit/burn unit provides the ideal environment for management of the extensive loss of skin and has From the Department of Dermatology,a Department of Surgery and the Intermountain Burn Center,b University of Utah School of Medicine. Funding sources: None. Conflicts of interest: None identified. Accepted for publication April 12, 2002. Reprint requests: John J. Zone, MD, Chairman, Department of Dermatology, University of Utah School of Medicine, 50 N Medical Dr, Salt Lake City, UT 84132. E-mail: [email protected]. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/1/127249 doi:10.1067/mjd.2002.127249

548

improved the overall outcome and survival of these patients.3,4 However, despite optimal wound care, fluid management, and control of infection, TEN has a mean mortality rate of approximately 30%, with some series reporting as high as 60% to 70% mortality.2 The majority of patients, including children, die from complications of infections. Therapy for TEN is primarily aimed at supportive care, and there are no specific treatments. There are several case reports and small series of patients treated with immunosuppressive agents such as cyclosporine,5,6 cyclophosphamide,5 thalidomide,7 and other measures such as plasmapheresis.8,9 The use of corticosteroids in the treatment of TEN in adults and children remains controversial and may result in a higher incidence of complications.10,11 Intravenous immunoglobulin (IVIg) is composed primarily of highly purified polyspecific IgG from pooled human serum. IVIg has immunomodulating properties and has been shown to be effective in the treatment of a variety of dermatologic and nondermatologic conditions, including immunodeficiencies, Kawasaki’s disease,12 dermatomyositis,13,14 and immunobullous diseases.15 Administration of IVIg has recently been shown to result in rapid improvement in a series of 8 adult and 2 pediatric patients with TEN.16 In addition, several case reports of the benefit of IVIg in the treatment of TEN have been published.17-19 We present a series of 8 pediatric

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Table I. Characteristics of pediatric patients with TEN who were treated with IVIg Patient No.

1 2 3 4 5 6 7 8

Age/Sex

Etiology

3 y/M Penicillin 14 y/F Phenobarbital 4 y/M Unknown 4 y/M Penicillin 33 mo/F TMP/sulfa 22 mo/M E-mycin/sulfa

%BSA/No. LOS Time to tx of MM (days) (days)

Time arrest (days)

Time heal (days)

Dose of IVIg (g/kg/d)

No. of doses

Complications

96/2 60/2 43/2 ⬎90/2 30/2 ⬎90/1

22 19 9 4 18 23

4 3 2 3 2 5

2 3 2 1 3 4

7 14 7 4 11 10

0.5 0.5 0.5 0.75 0.75 0.5

4 4 4 4 4 7

60/2

9

2

1

9

0.5

4

Line sepsis* Moraxella/sputum None None G⫹ bacteremia Respiratory MRSA infection, DVT None

70/2

5

5

1

3

0.5

4

None

21 y/F Carbamazepine (Tegretol) 14 y/F Lamotrigine

BSA, Body surface involvement; DVT, deep venous thrombosis; E-mycin/sulfa, erythromycin/sulfisoxazole; G⫹, gram-positive; LOS, length of hospital stay; MM, mucous membranes involved; MRSA, methicillin-resistant Staphylococcus aureus; time to tx, time from appearance of first skin lesions to initiation of therapy; time arrest, time from start of IVIg treatment to interruption of further progression of skin lesions; time heal, time between start of IVIg treatment to complete skin healing (re-epithelialization); TMP/Sulfa, trimethoprim/Sulfamethoxazole. *Enterobacter cloacae cultured from indwelling catheter.

patients with TEN who were safely and effectively treated with IVIg between 1999 and 2001.

PATIENTS AND METHODS This retrospective study was approved by the Institutional Review board of the University of Utah Medical Center. We reviewed the charts of 8 pediatric patients who were admitted between June 1999 and March 2001 with a diagnosis of TEN, who were identified from the computerized records of the University of Utah Health Sciences Center, Primary Children’s Medical Center, and Intermountain Burn Center. In addition, 3 additional pediatric patients with TEN who were not treated with IVIg between 1988 and 1998 were identified and studied as historical controls. The diagnosis of TEN was based on the clinical findings of acute, widespread epidermal sloughing, involving ⬎10% of body surface area (BSA). In all cases, a biopsy was performed that showed the characteristic findings of necrotic keratinocytes, dermal inflammation, and dermoepidermal separation. Direct immunofluoresence, when performed, was negative. For each patient the following information was obtained: age, sex, duration of hospital stay, implicated drug, percentage of BSA involved, number of mucous membranes involved, need for mechanical ventilation, presence of severe leukopenia (white blood cell count, ⬍1000 cells/␮L), infectious complications (including organisms), and disposition. In addition, the time from initiation of symptoms of TEN to initiation of therapy (time to treatment), time to arrest of disease progression after initiation of therapy, and time to complete re-epithelialization were recorded. Patients admitted to the Intermountain Burn Cen-

ter were treated by an established protocol that involved initial surgical treatment with mechanical debridement of necrotic tissues and coverage of the denuded areas with Biobrane, a semisynthetic wound dressing (Winthrop Pharmaceuticals, New York, NY). Corticosteroids and all unnecessary medications were discontinued. Systemic antibiotics were not given prophylactically, but were administered for signs of infection. Skin, blood, and urine cultures were routinely performed. Fluid resuscitation and nutritional support were addressed early and aggressively. Patients admitted to the Primary Children’s Medical Center underwent a similar protocol, except for debridement and Biobrane placement. All patients were evaluated and followed up closely by the dermatology service; biopsy specimens for histology and immunofluorescence were obtained. The ophthalmology service was consulted for eye care. Since June 1998, all patients admitted to the University Burn center with TEN have been treated with IVIg, 0.5 to 0.75 g/kg per day for 4 consecutive days, based on the protocol published by Viard et al.16 Administration of IVIg was preapproved by the Pharmacy and Therapeutics Committee of the University Hospital. No additional therapeutic agents were given. Patients in the historical group were treated with a similar protocol, but received treatment with plasmapheresis, as opposed to IVIg.

RESULTS The demographic and clinical characteristics of patients treated with IVIg are summarized in Table I. There were 4 male and 4 female patients, with a mean age of 8.1 years (range, 22 months to 21 years). Antibiotics were implicated in 4 cases (pen-

550 Tristani-Firouzi et al

icillin in 2 cases, sulfonamides in 2 cases) and anticonvulsants in 3 cases (phenobarbital, carbamazepine, lamotrigine); in one case a specific inciting factor could not be determined. Widespread epidermal necrosis was noted in all patients with mean BSA involvement of 67% (range, 30%-90%). Mucous membrane involvement was present in all patients. Six patients were admitted to the University of Utah Hospital burn center and two patients were admitted to the Primary Children’s Medical Center intensive care unit and evaluated by the University burn team. The average length of time between onset of symptoms/signs of TEN to admission to hospital and onset of treatment was 3.2 days (range, 2-5 days). The average time to arrest of progression, defined as length of time from start of therapy to when no further epidermal detachment or new blistering were noted, was 2.1 days (range, 1-4 days). Furthermore, the average time to complete re-epithelialization was 8.1 days (range, 3-14 days). Most patients received the established 4-day course of IVIg, except for patient 7 (see Table I) who received 7 days of IVIg because she had a slightly longer time to arrest of lesions (4 days vs mean of 2.1 days). One patient (No. 8) had received one dose of intravenous steroids, which was discontinued upon admission. The average length of hospital stay was 13.6 days (range, 4-23 days). There was no mortality in our series. Four patients required mechanical ventilation (data not shown). All patients were discharged to home, except for one patient (No. 6) who was discharged to an intermediate care facility for ease of follow-up. IVIg therapy was well tolerated and there were no episodes of vasomotor symptoms, worsening renal function, or severe allergic reactions. As can be appreciated from the data, in several cases the length of hospitalization was greater than the time for complete skin healing. Enterobacter cloacae was cultured from an indwelling catheter in patient 1, requiring treatment with gentamicin. Moraxella sp was cultured from the sputum of patient No. 2. Patient No. 5 developed Staphylococcus aureus bacteremia. Patient No. 6 developed a methicillin-resistant S aureus respiratory infection treated with vancomycin, in addition to deep venous thrombosis in the subclavian vein, requiring anticoagulation with heparin. Severe leukopenia (⬍1000 cells/␮L) did not develop in any of the patients; however, 2 patients had a white blood cell count of ⬍2000/␮L by the 2nd day of admission, which normalized by day 5 (data not shown). Other potential side effects of IVIg, including anaphylactic reactions, nephrosis, hemolysis, vasomotor symptoms such as headaches or nausea, were not noted in the patients. Three pediatric patients with TEN were treated

J AM ACAD DERMATOL OCTOBER 2002

before 1998 with plasmapheresis. The average BSA involvement in this group was 38%, with 100% survival. The mean time to arrest in progression of lesions in this group was 4.5 days, and mean for complete re-epithelialization was 11.7 days.

DISCUSSION We present a series of 8 pediatric patients who were treated with IVIg for TEN. Despite significant BSA involvement, all patients survived. In addition, treatment with IVIg resulted in arrest in progression of TEN (mean, 3.2 days) and rapid re-epithelialization (mean complete recovery, 8.1 days), without any toxicity from the drug treatment. These results are in agreement with Viard et al16 who reported the successful treatment of 8 adult and 2 pediatric TEN patients with IVIg (dosage, 0.2-0.75 g/kg/day for 4 days). In this series the mean time for response and complete re-epithelialization were 1.5 and 6.9 days, respectively. Although TEN is considered a severe, idiosyncratic drug reaction, its pathophysiology remains unknown. Recent studies suggest that TEN may be mediated via apoptosis or programmed cell death pathways. Keratinocytes from patients with TEN have been shown to undergo extensive apoptosis, mediated via specialized cell-membrane bound receptors such as Fas (CD95).20 Viard et al16 demonstrated that keratinocytes from TEN patients show up-regulation of lytically active Fas ligand (FasL) expression. In addition, keratinocyte death in culture could be inhibited by IVIg via inhibition of Fas-FasL interaction. Therefore the therapeutic effects of IVIg may be mediated by binding of naturally occurring Fas-blocking antibodies present in the IVIg to Fas. Other cytokines, such as tumor necrosis factor ␣ (TNF-␣), which are elaborated by CD8⫹ and natural killer cells, may also be responsible for apoptosis as well.20 Other proposed mechanisms of action of IVIg therapy include elimination of circulating immune complexes, modulation of cytokine milieu, functional blockade of antibody Fc receptors, and regulation of cellular immune responses.15,21 Currently there are no specific treatments for TEN and the only published randomized placebo-controlled trial testing the efficacy of thalidomide was discontinued as a result of increased mortality in the treatment arm.7 There are several open-label, retrospective series and case reports published on the treatment of TEN in adults with cyclosporine, plasmapheresis, cyclophosphamide, and corticosteroids. The results of several pediatric case series of TEN are summarized in Table II. Sheridan et al22 reported on a series of 10 children with widespread TEN who

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Table II. Clinical summary of published series of pediatric patients with TEN Authors

Sheridan et al22 Prendiville et al23 Taylor et al3 Revuz et al24 Ruiz-Maldonado25 Ruiz-Maldonado25

No. of patients

Mean %BSA

%Mortality

Mean LOS (days)

Time arrest (days)

Time heal (days)

Comments

10 7 6 13 5 16

76 NR 72.5 NR 88 83

0 0 16 0 60 37.5

19.3 14.3 22.7 NR NR NR

NR NR NR NR NR NR

NR NR 14 NR NR NR

Supportive care Supportive care/ND Porcine xenograft Supportive care/ND ND SJS-TEN subset

LOS, Length of hospital stay; ND, patients not debrided; NR, data not recorded for series; SJS, Stevens-Johnson syndrome; time arrest, time from start of treatment to interruption of further progression of skin lesions; time heal, time to complete skin healing (re-epithelialization).

were treated in a burn unit setting with symptomatic management only. All patients survived with an average length of hospitalization of 19.3 days. In a retrospective study by Prendiville et al,23 7 pediatric patients with TEN who were admitted to the pediatric intensive care unit or medical ward were treated symptomatically without debridement, with an average hospital stay of 14.3 days and 100% survival. This group advocated that with meticulous wound care, children with TEN can be adequately cared for outside the burn unit. In another series by Taylor et al,3 6 children with extensive TEN were treated symptomatically and covered by a porcine xenograft after debridement. They reported a mean time for complete re-epithelialization of 14 days from placement of xenografts, a mean length of hospitalization of 22.7 days, and a mortality rate of 16%. In a study by Revuz et al,24 no mortality was reported in a subset of 13 pediatric patients. However, the mortality rate reported in a series of patients published by Ruiz-Maldonado25 was higher: 60% in a series with TEN, and 37.5% in patients with Stevens-Johnson syndrome–TEN overlap; sepsis was the overwhelming cause of death. These patients were symptomatically treated in an intensive care unit setting and did not undergo debridement. Given the multiple variables and differences in the treatment protocols, it is difficult to compare our results with these published series. We have also evaluated the data from 3 pediatric patients with TEN who were treated in our burn unit with plasmapheresis before 1998. In this group, the mean time to arrest in progression of lesions was 4.5 days (compared with 2.1 days for IVIg treatment) and mean time to complete epithelialization was 11.7 days (compared with 8.3 days for IVIg treatment). However, given the small number of patients in this historical group, statistical comparison is not possible. In addition, these patients received fresh-frozen plasma at the completion of plasmapheresis treatments, which may act via similar mechanisms to IVIg in treatment of TEN.

The complications in our series were primarily infectious, including gram-negative and gram-positive bacteremia and respiratory tract infections. One patient developed deep venous thrombosis requiring short-term anticoagulation with heparin. A potential risk for cardiovascular and thromboembolic events exists with large doses of IVIg because it increases blood viscosity.26 It is interesting that this patient had received 7 doses of IVIg, compared with the standard 4-day course, potentially contributing to the formation of deep venous thrombosis. Other potential side effects of IVIg therapy that did not develop in our patients include renal failure secondary to osmotic nephrosis, hemolysis, aseptic meningitis, vasomotor symptoms, and anaphylactic reactions.15 On the basis of our results, we conclude that IVIg therapy is safe and effective for TEN in the pediatric population, resulting in rapid arrest in disease progression and rapid re-epithelialization. These results are comparable with those of previously published series of IVIG in the treatment of TEN in adults. Given the lack of uniformity in the treatment of TEN, there clearly exists the need for well-established, multicenter, controlled, randomized studies to test the effectiveness of IVIg therapy versus other modalities. REFERENCES 1. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-7. 2. Wolkenstein P, Revuz J. Toxic epidermal necrolysis. Dermatol Clin 2000;18:485-95, ix. 3. Taylor JA, Grube B, Heimbach DM, Bergman AB. Toxic epidermal necrolysis. A comprehensive approach. Multidisciplinary management in a burn center. Clin Pediatr (Phila) 1989;28:404-7. 4. Yarbrough DR 3rd. Experience with toxic epidermal necrolysis treated in a burn center. J Burn Care Rehabil 1996;17:30-3. 5. Arevalo JM, Lorente JA, Gonzalez-Herrada C, Jimenez-Reyes J. Treatment of toxic epidermal necrolysis with cyclosporin A. J Trauma 2000;48:473-8. 6. Paquet P, Pierard GE. Would cyclosporin A be beneficial to mitigate drug-induced toxic epidermal necrolysis? Dermatology 1999;198:198-202.

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7. Wolkenstein P, Latarjet J, Roujeau JC, Duguet C, Boudeau S, Vaillant L, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998;352:1586-9. 8. Egan CA, Grant WJ, Morris SE, Saffle JR, Zone JJ. Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 1999;40:458-61. 9. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol 1985;121:1548-9. 10. Halebian PH, Corder VJ, Madden MR, Finklestein JL, Shires GT. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986;204:503-12. 11. Smoot EC 3rd. Treatment issues in the care of patients with toxic epidermal necrolysis. Burns 1999;25:439-42. 12. Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991;324:1633-9. 13. Gottfried I, Seeber A, Anegg B, Rieger A, Stingl G, Volc-Platzer B. High dose intravenous immunoglobulin (IVIG) in dermatomyositis: clinical responses and effect on sIL-2R levels. Eur J Dermatol 2000;10:29-35. 14. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000. 15. Rutter A, Luger TA. High-dose intravenous immunoglobulins: an approach to treat severe immune-mediated and autoimmune diseases of the skin. J Am Acad Dermatol 2001;44:101024. 16. iard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95

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