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Drug-induced toxic epidermal necrolysis in children
Drug-Induced Toxic Epidermal Necrolysis in Children By William G. Jones, Paul Halebian, Michael Madden, Jerome Finkelstein, and Cleon W. G o o d w i n N e w York, N e w York
9 Nine pediatric patients with drug-induced toxic epidermal necrolysis w e r e treated w i t h a regimen of basic burn care and without the use of steroids or topical or systemic antimicrobial agents. Although septic complications continue to occur frequently, infections are better tolerated w h e n potential iatrogenic sources of decreased host resistance, such as steroids, are eliminated. Neutropenia, gram-negative sepsis, and mortality w e r e all greatly reduced with this regimen, while healing was neither impaired nor prolonged. Thus, steroids and sulfa-containing topical agents should be avoided in the t r e a t m e n t of this disorder. 9 1989 by Grune R, Stratton, Inc. INDEX W O R D S : Toxic epidermal necrolysis; burn care.
OXIC E P I D E R M A L N E C R O L Y S I S ( T E N ) is a
severe exofoliative dermatologic disorder of T undetermined pathophysiology, probably representing a severe variant of the Stevens-Johnson Syndrome.' Implicated etiologic agents include drugs, infections, and vaccinations. In many cases, no clear cause can be determined. Although drug-induced T E N appears to be a common etiologic variety in adults, it has been reported only infrequently in children. 25 TEN is characterized by the acute onset of a generalized rash of discrete and confluent erythematous areas that evolve into easily ruptured bullae. This results in a painful loss of the affected epidermis. Mucosal and ocular involvement are frequent, and fever and systemic toxicity are often present. A virallike prodrome may precede the development of skin manifestations. Significant morbidity and mortality, often related to secondary bacterial infection, have been the rule) '2'6 The clinical diagnosis can be confirmed by a punch biopsy of affected areas demonstrating a dermal/epidermal cleavage plane upon either routine or frozen sectioning. 7'8 The differential diagnosis of T E N in children includes the staphylococcal scalded skin syndrome (SSSS). 1 This entity is more common in pediatric patients, and is accompanied by marked cutaneous tenderness. Its etiology, as the name implies, is related to a staphylococcal infection, and there is relative sparing of the mucosal surfaces. The cleavage plane in SSSS is intraepidermal, 8 and associated morbidity and mortality are low if appropriate antibiotics are administered. 9 Because of the similarity of skin lesions in T E N to partial-thickness thermal injuries, children with extensive involvement often require treatment in specialized burn care facilities. 2'3'6'~~ The role of the surgeon is Journalof Pediatric Surgery, Vol 24, No 2 (February), 1989: pp 167-170
crucial because of the attendant fluid and nutritional requirements, the need for temperature maintenance and control of evaporative losses, the potential requirement for specialized wound care techniques, and the need for a coordinated team approach to the care of the patient. Previous recommendations for treatment of druginduced T E N have included the use of high-dose corticosteroid therapy of up to 1,000 mg of hydrocortisone per day, 1216based on the concept of the disease as a delayed-type hypersensitivity reaction. Because of frequent associated infectious complications, topical antimicrobial therapies such as silver sulfadiazine and prophylactic systemic antibiotics have also been employed. 6,17,18 Previous observations at this institution of patients with T E N who were treated with steroids (primarily adults) have been notable for high septic mortality rates, with 100% mortality in pediatric patients with >40% total body surface area involvement of the disease 2 (Table 1). In comparison with burned patients treated in this institution with similarly sized injuries, infectious complications in patients with steroidtreated T E N appeared more virulent and less responsive to conventional therapy, even given the welldocumented immunodeficiencies of the burned patient. Gram-negative infections were the most common cause of death, and often temporally associated with neutropenia. The rationale that basic techniques of burn care were applicable to the patient with T E N , and the presumption that the use of corticosteroids was a source of considerable iatrogenic morbidity led to the creation of a new treatment protocol for patients with TEN. Use of this protocol in adults has been previously reported. 19 In this report, we present the results of its use in a pediatric population. MATERIALS A N D METHODS
Patients were admitted usually following transfer from referring institutions, and a biopsy confirmed the diagnosis. Areas of necrotic epidermis and ruptured bullae were debrided initially and open
From The Burn Center, Department o f Surgery, The New York Hospital-Cornell University Medical Center, New York City. Address reprint requests to Cleon IV. Goodwin, MD, The Burn Center, The New York Hospital, Department o f Surgery, 525 E 68th St, New York, N Y IO021. 9 1989 by Grune & Stratton, Inc. 0022-3468/89/2402-0006503.00/0 167
168
JONES ET AL
Table 1. Previous Experience W i t h TEN in Pediatric Patients at the N e w York Hospital Burn Center Extent of Patient Slough Age (yr)/Sex (% TSSA) 17/M
80
Etiology
Steroid Dose*
AMP
480
Associated Diseases --
18/M
90
DIL, PBARB
400
Good-Pasture's
4/F
90
TMP/SMX
240
--
17/F
40
?
140
SLE
Table 3. Infectious Complications
Outcome Died, gr-sep Died, gr-sep Died, gr-sep Survived
Abbreviations: % TBSA, percent total body surface area; gr-sep, gram-negative sepsis; AMP, ampicillin; DIL, Dilantin; PBARB, phenobarbital; TMP/SMX, trimethoprim/sulfamethoxazole. *rag hydrocortisone equivalent per day.
wounds were covered with emollient impregnated gauze dressings. Vigorous fluid resuscitation, nutritional support, and temperature maintenance were provided as for burned patients. Corticosteroids were not used for treatment, and if begun at the referring institution, doses were rapidly tapered and discontinued. Prophylactic and topical antibiotics were not used, but at the first sign of infection, appropriate cultures and gram stains were obtained, and broad-spectrum presumptive antibiotic therapy was begun. If the wound was clinically implicated as the source of infection, topical therapy was changed to 0.5% silver nitrate soaked dressings. RESULTS
From 1982 through 1985, nine pediatric patients with TEN were treated in this fashion (Table 2). Four patients were initially given high-dose steroids at the referring institution. Steroids were rapidly tapered and discontinued in all but the patient suffering from concomitant systemic lupus erythematosus (SLE), who was continued on low-maintenance doses. Five patients received no steroids throughout their course. The average time from administration of the implicated etiologic agent to onset of skin manifestations was nine days. Three patients had a viral-like proTable 2. Drug-Induced TEN in Pediatric Patients Treated
Patient Age/Sex
Bacteremia
Primary Source
17 y r / M
S aureus
13 y r / M 7 yr/F
S aureus
Septic thrombophlebitis Pneumonia Pneumonia
-E coil S fecalis
6 mo/F 16 yr/F 13 yr/F 18 y r / M
Line sepsis Pneumonia Urinary tract Line sepsis
S aureus S aureus E coil S aureus
drome, consisting of sore throat and dry cough, that preceded the appearance of skin lesions. Immunofluorescence studies of skin punch biopsies were variable and nonspecific, although the patient with SLE demonstrated deposition of IgG and C3 complexes at the epidermal/dermal junction. The average time to healing of skin lesions was 14 days, and no patient demonstrated progression of skin slough beyond three days after admission. Seven patients (78%) required systemic antibiotics for documented infections (Table 3). Staphylococcus aureus was the most common infecting organism; gram-negative infections were virtually eliminated. Pneumonia was the most common source of infection in these patients, while no patient had objective evidence of wound infection. Five patients had a prompt response to appropriate systemic antibiotics, while one patient who was Arrows ( ~ ) mark the appearance positive blood
A" E E tO
of
cultures Patient
50 ~,
2~7 5W
25 5e
6& 70 80
Without Steroids
'~ 0
Patient Age/Sex
Extent of Slough (% TBSA)
17 yr/M 13 yr/M 7 yr/F
90 50 90
TEG TEG PCN
+ + -
----
6 mo/F
40
-
AIDS
16 13 18 10 14
60 50 40 50 70
TMP/ SMX DIL PBARB AMP PBARB DIL
Survived Survived Died, grsep Survived
+ --
SLE -----
Survived Survived Survived Survived Survived
yr/F yr/F yr/M yr/F yr/F
Etiology
Associated Prodrome Diseases
Outcome
Abbreviations: % TBSA, percent total body surface area; gr-sep, gram-negative sepsis; TEG, Tegretol; PCN, Penicillin; TMP/SMX, trimethoprim/sulfamethoxazole; DIL, Dilantin; PBARB, phenobarbital; AMP, ampicillin.
20
,
9V
E
u 0
10
--0
5
O F-
~.~._~ Deoth 2
.5
l
I
I
l
I
I
I
4
5
6
7
8
9
10
Hospital dQy Fig 1. Total leukocyte counts in pediatric patients undergoing treatment for drug-induced toxic epidermal necrolysis.
TOXIC EPIDERMAL NECROLYSIS
169 Table 4. Other Complications
Arrows (4) rnork the oppeoronce of positive blood cultures P o tient
30 2~7 4m
5e
E 25 E
6&
20
80 9V
7n ~
o
o 0 ~- -
10
O. 0
"5
Complication
No. of Patients
Mucous membrane involvement Mild Severe Ocular involvement Conjunctivitis Corneal slough Ankylosymblepheron Transient elevation in LFT Coagulopathy Skin complications Alopecia Hyperpigmentation Hypertrophic scarring Esophageal slough Upper gastrointestinal bleeding
9 (6) (3) 9 (7) (2) ( 1) 6 4 3 (2) (2) ( 1) 1 1
Abbreviation: LFT, liver function tests.
5
Z
I
I
I
I
I
I
I
I
I
2
5
4
5
6
7
8
9
I0
H o s p i t o l doy Fig 2. Absolute neutrophil counts in pediatric patients undergoing treatment for drug-induced toxic epidermal necrolysis.
received in a moribund state of septic shock died within hours of admission. An additional patient failed to respond to antibiotics until a focus of septic thrombophlebitis was identified and the affected vein was excised. Neutropenia was noted only in the patient who died; all others had appropriate increases in their total WBC count (Fig 1) and neutrophil counts in response to infection (Fig 2). Noninfectious complications were also frequent, and are listed in Table 4. DISCUSSION
The term toxic epidermal necrolysis was introduced by Lyell2~ in 1956 to describe a clinical syndrome of devastating dermatitis progressing to epidermal sloughing that resembled a scald injury. The later differentiation between the disease we currently describe as TEN and the SSSS resulting from infections with certain phage group II S aureus organisms was an important advances since both the therapy and prognosis are vastly dissimilar. 2~ The exact pathophysiology of drug-induced TEN remains uncertain. Previous reports have suggested a possible association with autoimmune disease and a predisposition created by viral infections. 1'16'22 A hypersensitivity/immunologic mechanism has long been postulated but never proven. 14'23 Although an immunologic mechanism is supported by the appearance of TEN in bone marrow transplant patients and experimental models of graft v host disease, immuno-
fluoresence studies of skin biopsies from TEN patients have been variable. 24'25 Prior reports of TEN in children have been associated with mortality rates of 25% to 75%. 2"4'1~ Most deaths were sepsis-related, and most of the patients had been treated with high-dose steroids. In our own experience, the use of steroids increased the risk of septic complications and mortality in TEN patients? A mortality rate in this series of 11% represents a significant improvement, and it can only be speculated that if the single patient who died had been received earlier, mortality might have been avoided. The salvage of six patients with lesions involving >__50% of their total body surface area, including one patient with a 90% slough, is a marked improvement over our previous results in patients treated with steroids, in whom none with lesions of >40% involvement survived. We feel that improvement in survival in this series resulted from the elimination of an iatrogenic source of decreased host resistance rather than an effect on the primary disease process itself. The infection rate continues to be high, but the infections are less severe and predominantly due to gram-positive organisms rather than the more deadly opportunistic gram-negative bacteria. As in burn patients, pneumonia and invasive catheters are an important source of septic complications. Earlier recognition of sepsis is also possible in patients treated without steroids, as these drugs may mask the earliest signs of infection. The efficacy of steroids must also be considered doubtful in light of reports of TEN in patients already receiving therapeutic doses of corticosteroids for treatment of other disorders. 1,19 Patients in this series were treated without the routine use of topical antimicrobial agents because in theory, and in our own experience, the superficial nonescharotic epidermal lesions of TEN that spare the
170
JONES ET AL
dermis and its v a s c u l a t u r e are less susceptible to infection than t h e r m a l injuries. It would seem only logical to avoid the use of sulfa-containing topicals such as silver s u l f a d i a z i n e since sulfa drugs a r e one of the i m p l i c a t e d etiologic agents in T E N . N o differences in healing time, wound infections, or long-term complications were noted between f o r m e r patients t r e a t e d with topical a n t i m i c r o b i a l agents and those in the present study group. N e u t r o p e n i a has been previously observed as a frequent complication in patients with T E N , and a sign of a poor prognosis. 17N e u t r o p e n i a was not noted in this series except in one p a t i e n t whose condition was complicated by overwhelming sepsis; sepsis m a y l e a d to consumptive neutropenia, and it was the most likely cause in this p a t i e n t ' s case. Steroids and silver sulfadiazine have also been associated with alterations in leukocyte counts19'26; thus, n e u t r o p e n i a observed in m a n y previously r e p o r t e d patients m a y have been a complication of their t h e r a p y . T h e description of neutropenia in a d u l t p a t i e n t s with T E N who h a d no a p p a r e n t sepsis, and who were not receiving either steroids or sulfa-containing topical agents, has raised
speculation t h a t n e u t r o p e n i a m a y be a manifestation of the p r i m a r y disease process. 1~ A l t h o u g h such a "prim a r y n e u t r o p e n i a " has never been proven and is not suggested by the present series, it could also be a r g u e d that children m a y be m o r e resistant to this effect than adults. Nonetheless, we feel t h a t the finding of neutropenia should be treated as a sign of sepsis until proven otherwise. T r a n s i e n t elevations in liver function tests and mild increases in the p r o t h r o m b i n t i m e s of patients with T E N have been previously observed at this institution. 2'19 T h e etiology of these findings is unclear, although it m a y be r e l a t e d to the p r i m a r y disease process. A r e g i m e n of t h e r a p y relying on basic principles of t r e a t m e n t of p a r t i a l - t h i c k n e s s e p i d e r m a l wounds, avoidance of the use of p o t e n t i a l l y complicating drugs such as steroids and topical sulfa compounds, and aggressive t r e a t m e n t of infection has resulted in a m a r k e d i m p r o v e m e n t in our a b i l i t y to care for pediatric patients with d r u g - i n d u c e d T E N . F u r t h e r improvements m a y only come with a g r e a t e r u n d e r s t a n d i n g of the p a t h o p h y s i o l o g y of the disease process itself.
REFERENCES
1. Rasmussen J: Toxic epidermal necrolysis. Med Clin North Am 64:901-920, 1980 2. Halebian P, Corder V, Herndon D, et al: A burn unit experience with toxic epidermal necrolysis. J Burn Care Rehabil 4:176183, 1983 3. Adzick NS, Kim SH, Bondoc CC, et al: Management of toxic epidermal necrolysis in a pediatric burn center. Am J Dis Child 139:499-502, 1985 4. Rosenthal AL, Binnick S, Panzer P, et al: Drug-induced toxic epidermal necrolysis in children: Report of two cases. Cutis 24:437440, 1979 5. Manzella JP, Hall CB, Green JL, et al: Toxic epidermal necrolysis in childhood: Differentiation from staphylococcal scalded skin syndrome. Pediatrics 66:291-294, 1980 6. 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 4:91-100, 1983 7. Amon RB, Dimond RL: Toxic epidermal necrolysis: Rapid differentiation between staphylococcal- and drug-induced disease. Arch Dermatol 111:1433-1437, 1975 8. Honig PJ, Gaisin A, Buck BE: Frozen section differentiation of drug-induced and staphylococcal-induced toxic epidermal necrolysis. J Pediatr 92:504-505, 1978 9. Rasmussen J: Toxic epidermal necrolysis: A review of 75 cases in children. Arch Dermatol 111:1135-1139, 1975 10. Marvin JA, Heimbach DM, Engrav LH, et al: Improved treatment of the Stevens-Johnson syndrome. Arch Surg 119:601605, 1984 11. Demling RH, Ellerbe S, Lowe N J: Burn unit management of toxic epidermal necrolysis. Arch Surg 113:758-759, 1978 12. Bjornberg A: Fifteen cases of toxic epidermal necrolysis. Acta Derm Venereol 53:149-152, 1973 13. Finlay AY, Richards J, Holt PJ: Intensive therapy unit management of toxic epidermal necrolysis: Practical aspects. Clin Exp Dermatol 7:55-60, 1983
14. Simons HN: Acute life-threatening dermatologic disorders. Med Clin North Am 65:227-243, 1981 15. Ohlenschlaeger K: Toxic epidermal necrolysis and StevensJohnson disease. Acta Derm Venereol 46:205-209, 1966 16. Lyell A: Toxic epidermal necrolysis (the scalded skin syndrome): A reappraisal. Br J Dermatol 100:69-81, 1979 17. Westly ED, Wechsler HL: Toxic epidermal necrolysis: Granulocytic leukopenia as a prognostic indicator. Arch Dermatol 120:721-726, 1984 18. Fligner CL, Jack R, Twiggs GA, et al: Hyperosmolality induced by propylene glycol: A complication of silver sulfadiazine therapy. JAMA 253:1606-1609, 1985 19. Halebian P, Corder V, Madden M, et al: Toxic epidermal necrolysis. Ann Surg (in press). 20. Lyell A: Toxic epidermal necrolysis: An eruption resembling scalding of the skin. Br J Dermato168:355-361, 1956 21. Melish ME, Glasgow LA: The staphylococcal scalded skin syndrome: Development of an experimental model. N Engl J Med 282:1114-1119, 1970 22. Kauppinen K: Cutaneous reactions to drugs with special reference to severe muco-cutaneous bullous eruptions and sulphonamides. Acta Derm Venereol 68:1-89, 1972 23. Tagami H, Tatsuta K, Iwatski K, et al: Delayed hypersensitivity in ampicillin-induced toxic epidermal necrolysis. Arch Dermatol 119:910-913, 1983 24. Stein KM, Sihlappner OI, Heaton CL, et al: Demonstration of basal cell immunofluorescence in drug-induced toxic epidermal necrolysis. Br J Dermato186:246-252, 1972 25. Tsoi M, Storb R, Jones E, et al: Deposition of IgM and complement at the dermo-epidermal junction in acute and chronic graft-vs-host disease in man. J Immunol 120:1485, 1978 26. Jarrett F, Ellerbe S, Demling RH: Acute leukopenia during topical burn therapy with silver sulfadiazine. Am J Surg 135:818819, 1978
9 Nine pediatric patients with drug-induced toxic epidermal necrolysis w e r e treated w i t h a regimen of basic burn care and without the use of steroids or topical or systemic antimicrobial agents. Although septic complications continue to occur frequently, infections are better tolerated w h e n potential iatrogenic sources of decreased host resistance, such as steroids, are eliminated. Neutropenia, gram-negative sepsis, and mortality w e r e all greatly reduced with this regimen, while healing was neither impaired nor prolonged. Thus, steroids and sulfa-containing topical agents should be avoided in the t r e a t m e n t of this disorder. 9 1989 by Grune R, Stratton, Inc. INDEX W O R D S : Toxic epidermal necrolysis; burn care.
OXIC E P I D E R M A L N E C R O L Y S I S ( T E N ) is a
severe exofoliative dermatologic disorder of T undetermined pathophysiology, probably representing a severe variant of the Stevens-Johnson Syndrome.' Implicated etiologic agents include drugs, infections, and vaccinations. In many cases, no clear cause can be determined. Although drug-induced T E N appears to be a common etiologic variety in adults, it has been reported only infrequently in children. 25 TEN is characterized by the acute onset of a generalized rash of discrete and confluent erythematous areas that evolve into easily ruptured bullae. This results in a painful loss of the affected epidermis. Mucosal and ocular involvement are frequent, and fever and systemic toxicity are often present. A virallike prodrome may precede the development of skin manifestations. Significant morbidity and mortality, often related to secondary bacterial infection, have been the rule) '2'6 The clinical diagnosis can be confirmed by a punch biopsy of affected areas demonstrating a dermal/epidermal cleavage plane upon either routine or frozen sectioning. 7'8 The differential diagnosis of T E N in children includes the staphylococcal scalded skin syndrome (SSSS). 1 This entity is more common in pediatric patients, and is accompanied by marked cutaneous tenderness. Its etiology, as the name implies, is related to a staphylococcal infection, and there is relative sparing of the mucosal surfaces. The cleavage plane in SSSS is intraepidermal, 8 and associated morbidity and mortality are low if appropriate antibiotics are administered. 9 Because of the similarity of skin lesions in T E N to partial-thickness thermal injuries, children with extensive involvement often require treatment in specialized burn care facilities. 2'3'6'~~ The role of the surgeon is Journalof Pediatric Surgery, Vol 24, No 2 (February), 1989: pp 167-170
crucial because of the attendant fluid and nutritional requirements, the need for temperature maintenance and control of evaporative losses, the potential requirement for specialized wound care techniques, and the need for a coordinated team approach to the care of the patient. Previous recommendations for treatment of druginduced T E N have included the use of high-dose corticosteroid therapy of up to 1,000 mg of hydrocortisone per day, 1216based on the concept of the disease as a delayed-type hypersensitivity reaction. Because of frequent associated infectious complications, topical antimicrobial therapies such as silver sulfadiazine and prophylactic systemic antibiotics have also been employed. 6,17,18 Previous observations at this institution of patients with T E N who were treated with steroids (primarily adults) have been notable for high septic mortality rates, with 100% mortality in pediatric patients with >40% total body surface area involvement of the disease 2 (Table 1). In comparison with burned patients treated in this institution with similarly sized injuries, infectious complications in patients with steroidtreated T E N appeared more virulent and less responsive to conventional therapy, even given the welldocumented immunodeficiencies of the burned patient. Gram-negative infections were the most common cause of death, and often temporally associated with neutropenia. The rationale that basic techniques of burn care were applicable to the patient with T E N , and the presumption that the use of corticosteroids was a source of considerable iatrogenic morbidity led to the creation of a new treatment protocol for patients with TEN. Use of this protocol in adults has been previously reported. 19 In this report, we present the results of its use in a pediatric population. MATERIALS A N D METHODS
Patients were admitted usually following transfer from referring institutions, and a biopsy confirmed the diagnosis. Areas of necrotic epidermis and ruptured bullae were debrided initially and open
From The Burn Center, Department o f Surgery, The New York Hospital-Cornell University Medical Center, New York City. Address reprint requests to Cleon IV. Goodwin, MD, The Burn Center, The New York Hospital, Department o f Surgery, 525 E 68th St, New York, N Y IO021. 9 1989 by Grune & Stratton, Inc. 0022-3468/89/2402-0006503.00/0 167
168
JONES ET AL
Table 1. Previous Experience W i t h TEN in Pediatric Patients at the N e w York Hospital Burn Center Extent of Patient Slough Age (yr)/Sex (% TSSA) 17/M
80
Etiology
Steroid Dose*
AMP
480
Associated Diseases --
18/M
90
DIL, PBARB
400
Good-Pasture's
4/F
90
TMP/SMX
240
--
17/F
40
?
140
SLE
Table 3. Infectious Complications
Outcome Died, gr-sep Died, gr-sep Died, gr-sep Survived
Abbreviations: % TBSA, percent total body surface area; gr-sep, gram-negative sepsis; AMP, ampicillin; DIL, Dilantin; PBARB, phenobarbital; TMP/SMX, trimethoprim/sulfamethoxazole. *rag hydrocortisone equivalent per day.
wounds were covered with emollient impregnated gauze dressings. Vigorous fluid resuscitation, nutritional support, and temperature maintenance were provided as for burned patients. Corticosteroids were not used for treatment, and if begun at the referring institution, doses were rapidly tapered and discontinued. Prophylactic and topical antibiotics were not used, but at the first sign of infection, appropriate cultures and gram stains were obtained, and broad-spectrum presumptive antibiotic therapy was begun. If the wound was clinically implicated as the source of infection, topical therapy was changed to 0.5% silver nitrate soaked dressings. RESULTS
From 1982 through 1985, nine pediatric patients with TEN were treated in this fashion (Table 2). Four patients were initially given high-dose steroids at the referring institution. Steroids were rapidly tapered and discontinued in all but the patient suffering from concomitant systemic lupus erythematosus (SLE), who was continued on low-maintenance doses. Five patients received no steroids throughout their course. The average time from administration of the implicated etiologic agent to onset of skin manifestations was nine days. Three patients had a viral-like proTable 2. Drug-Induced TEN in Pediatric Patients Treated
Patient Age/Sex
Bacteremia
Primary Source
17 y r / M
S aureus
13 y r / M 7 yr/F
S aureus
Septic thrombophlebitis Pneumonia Pneumonia
-E coil S fecalis
6 mo/F 16 yr/F 13 yr/F 18 y r / M
Line sepsis Pneumonia Urinary tract Line sepsis
S aureus S aureus E coil S aureus
drome, consisting of sore throat and dry cough, that preceded the appearance of skin lesions. Immunofluorescence studies of skin punch biopsies were variable and nonspecific, although the patient with SLE demonstrated deposition of IgG and C3 complexes at the epidermal/dermal junction. The average time to healing of skin lesions was 14 days, and no patient demonstrated progression of skin slough beyond three days after admission. Seven patients (78%) required systemic antibiotics for documented infections (Table 3). Staphylococcus aureus was the most common infecting organism; gram-negative infections were virtually eliminated. Pneumonia was the most common source of infection in these patients, while no patient had objective evidence of wound infection. Five patients had a prompt response to appropriate systemic antibiotics, while one patient who was Arrows ( ~ ) mark the appearance positive blood
A" E E tO
of
cultures Patient
50 ~,
2~7 5W
25 5e
6& 70 80
Without Steroids
'~ 0
Patient Age/Sex
Extent of Slough (% TBSA)
17 yr/M 13 yr/M 7 yr/F
90 50 90
TEG TEG PCN
+ + -
----
6 mo/F
40
-
AIDS
16 13 18 10 14
60 50 40 50 70
TMP/ SMX DIL PBARB AMP PBARB DIL
Survived Survived Died, grsep Survived
+ --
SLE -----
Survived Survived Survived Survived Survived
yr/F yr/F yr/M yr/F yr/F
Etiology
Associated Prodrome Diseases
Outcome
Abbreviations: % TBSA, percent total body surface area; gr-sep, gram-negative sepsis; TEG, Tegretol; PCN, Penicillin; TMP/SMX, trimethoprim/sulfamethoxazole; DIL, Dilantin; PBARB, phenobarbital; AMP, ampicillin.
20
,
9V
E
u 0
10
--0
5
O F-
~.~._~ Deoth 2
.5
l
I
I
l
I
I
I
4
5
6
7
8
9
10
Hospital dQy Fig 1. Total leukocyte counts in pediatric patients undergoing treatment for drug-induced toxic epidermal necrolysis.
TOXIC EPIDERMAL NECROLYSIS
169 Table 4. Other Complications
Arrows (4) rnork the oppeoronce of positive blood cultures P o tient
30 2~7 4m
5e
E 25 E
6&
20
80 9V
7n ~
o
o 0 ~- -
10
O. 0
"5
Complication
No. of Patients
Mucous membrane involvement Mild Severe Ocular involvement Conjunctivitis Corneal slough Ankylosymblepheron Transient elevation in LFT Coagulopathy Skin complications Alopecia Hyperpigmentation Hypertrophic scarring Esophageal slough Upper gastrointestinal bleeding
9 (6) (3) 9 (7) (2) ( 1) 6 4 3 (2) (2) ( 1) 1 1
Abbreviation: LFT, liver function tests.
5
Z
I
I
I
I
I
I
I
I
I
2
5
4
5
6
7
8
9
I0
H o s p i t o l doy Fig 2. Absolute neutrophil counts in pediatric patients undergoing treatment for drug-induced toxic epidermal necrolysis.
received in a moribund state of septic shock died within hours of admission. An additional patient failed to respond to antibiotics until a focus of septic thrombophlebitis was identified and the affected vein was excised. Neutropenia was noted only in the patient who died; all others had appropriate increases in their total WBC count (Fig 1) and neutrophil counts in response to infection (Fig 2). Noninfectious complications were also frequent, and are listed in Table 4. DISCUSSION
The term toxic epidermal necrolysis was introduced by Lyell2~ in 1956 to describe a clinical syndrome of devastating dermatitis progressing to epidermal sloughing that resembled a scald injury. The later differentiation between the disease we currently describe as TEN and the SSSS resulting from infections with certain phage group II S aureus organisms was an important advances since both the therapy and prognosis are vastly dissimilar. 2~ The exact pathophysiology of drug-induced TEN remains uncertain. Previous reports have suggested a possible association with autoimmune disease and a predisposition created by viral infections. 1'16'22 A hypersensitivity/immunologic mechanism has long been postulated but never proven. 14'23 Although an immunologic mechanism is supported by the appearance of TEN in bone marrow transplant patients and experimental models of graft v host disease, immuno-
fluoresence studies of skin biopsies from TEN patients have been variable. 24'25 Prior reports of TEN in children have been associated with mortality rates of 25% to 75%. 2"4'1~ Most deaths were sepsis-related, and most of the patients had been treated with high-dose steroids. In our own experience, the use of steroids increased the risk of septic complications and mortality in TEN patients? A mortality rate in this series of 11% represents a significant improvement, and it can only be speculated that if the single patient who died had been received earlier, mortality might have been avoided. The salvage of six patients with lesions involving >__50% of their total body surface area, including one patient with a 90% slough, is a marked improvement over our previous results in patients treated with steroids, in whom none with lesions of >40% involvement survived. We feel that improvement in survival in this series resulted from the elimination of an iatrogenic source of decreased host resistance rather than an effect on the primary disease process itself. The infection rate continues to be high, but the infections are less severe and predominantly due to gram-positive organisms rather than the more deadly opportunistic gram-negative bacteria. As in burn patients, pneumonia and invasive catheters are an important source of septic complications. Earlier recognition of sepsis is also possible in patients treated without steroids, as these drugs may mask the earliest signs of infection. The efficacy of steroids must also be considered doubtful in light of reports of TEN in patients already receiving therapeutic doses of corticosteroids for treatment of other disorders. 1,19 Patients in this series were treated without the routine use of topical antimicrobial agents because in theory, and in our own experience, the superficial nonescharotic epidermal lesions of TEN that spare the
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dermis and its v a s c u l a t u r e are less susceptible to infection than t h e r m a l injuries. It would seem only logical to avoid the use of sulfa-containing topicals such as silver s u l f a d i a z i n e since sulfa drugs a r e one of the i m p l i c a t e d etiologic agents in T E N . N o differences in healing time, wound infections, or long-term complications were noted between f o r m e r patients t r e a t e d with topical a n t i m i c r o b i a l agents and those in the present study group. N e u t r o p e n i a has been previously observed as a frequent complication in patients with T E N , and a sign of a poor prognosis. 17N e u t r o p e n i a was not noted in this series except in one p a t i e n t whose condition was complicated by overwhelming sepsis; sepsis m a y l e a d to consumptive neutropenia, and it was the most likely cause in this p a t i e n t ' s case. Steroids and silver sulfadiazine have also been associated with alterations in leukocyte counts19'26; thus, n e u t r o p e n i a observed in m a n y previously r e p o r t e d patients m a y have been a complication of their t h e r a p y . T h e description of neutropenia in a d u l t p a t i e n t s with T E N who h a d no a p p a r e n t sepsis, and who were not receiving either steroids or sulfa-containing topical agents, has raised
speculation t h a t n e u t r o p e n i a m a y be a manifestation of the p r i m a r y disease process. 1~ A l t h o u g h such a "prim a r y n e u t r o p e n i a " has never been proven and is not suggested by the present series, it could also be a r g u e d that children m a y be m o r e resistant to this effect than adults. Nonetheless, we feel t h a t the finding of neutropenia should be treated as a sign of sepsis until proven otherwise. T r a n s i e n t elevations in liver function tests and mild increases in the p r o t h r o m b i n t i m e s of patients with T E N have been previously observed at this institution. 2'19 T h e etiology of these findings is unclear, although it m a y be r e l a t e d to the p r i m a r y disease process. A r e g i m e n of t h e r a p y relying on basic principles of t r e a t m e n t of p a r t i a l - t h i c k n e s s e p i d e r m a l wounds, avoidance of the use of p o t e n t i a l l y complicating drugs such as steroids and topical sulfa compounds, and aggressive t r e a t m e n t of infection has resulted in a m a r k e d i m p r o v e m e n t in our a b i l i t y to care for pediatric patients with d r u g - i n d u c e d T E N . F u r t h e r improvements m a y only come with a g r e a t e r u n d e r s t a n d i n g of the p a t h o p h y s i o l o g y of the disease process itself.
REFERENCES
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