Stevens-Johnson Syndrome in Thai Children A 29 ...

Stevens-Johnson Syndrome in Thai Children A 29-Year Study Srisupalak Singalavanija M D * , Wanida L i m p o n g s a n u r a k M D * * Dermatology Unit, Queen Sirikit National Institute of Child Health, College of Medicine, Rangsit University, Bangkok, Thailand

Background: Stevens-Johnson syndrome (SJS) is a rare and severe life-threatening hypersensitivity syruirome. The etiology is unclear hut is associated with drug exposure or infections and frequently high morbidity and mortality. Objective: To determine etiologies, treatments and comphcations of Stevens-Johnson syndrome (SJS) in children. Material and Method: A retrospective descriptive study was performed at Queen Sirikit National Institute of Child Health during 1979 and 2007 (29-year study). The authors collected and separated data into three phases from 1979 to 1987,1988 to 1997 and 1998 to 2007. Diagnosis was confirmed by pediatric dermatologists. Results: There were 189patients, 56 cases between 1979-1987, 72 cases between 1988-1997 and 61 cases between 19982(X)7. The ratio of male to female was 1.6:1. The range of age was from 2 months to 15 years old with a mean age of 5.5 years. One hundred and sixty-five cases (87%) had a history of drug taking before onset of the rash. The most common drugs exposure were antibiotics in 69 cases (42%c), anticonvulsant drugs in 58 cases (35%), non-steroids anti-inflammatory drugs in 8 cases (5%c), antimalarial drugs in 4 cases (2%c) and unknown drugs in 26 cases (16%>). Mycoplasma infections were found in 5 cases (3%). One hundred and nine cases (58%>) were treated with systemic corticosteroids. The corticosteroid treatment was increasing from 18%o in the first phase to 64%c and 87% in the second and third phase respectively. The overall complications were found in 38 cases (20%c) included bacterial skin infections in 16 cases (8%)), eye complications in 12 cases (6%>), hepatitis in 4 ca.ses (2%o) and other complications in 6 cases (2%^). Ten patients (5%) died from sepsis and underlying diseases. The mortality rale declined from 9%i in the first phase to 1.5% in the third phase Conclusion: Etiology of SJS in children was associated with drug exposure with the most commonly implicated drug being antibiotics and anticonvulsants. Corticosteroid may have a role in the treatment of SJS. Keywords: Stevens-Johnson syndrome. Children / Med Assoc Thai 2011; 94 (Suppl. 3): S85-S90 Full text. e-Journal: http://www.mat.or.th/journal

S t e v e n s - J o h n s o n S y n d r o m e ( S J S ) is a rare, ievere cutaneous adverse drug reaction potentially life:hreatening illness c h a r a c t e r i z e d by high fever a n d mucocutaneous involvement. The incidence of SJS is 1 -3 per million persons 3er year"'^'. Classification of S J S and T E N has b e e n rased on the d e g r e e of e p i d e r m a l d e t a c h m e n t ' ' ' . Epidermal d e t a c h m e n t of less than 1 0 % of the total lody surface area is considered SJS, more than 3 0 % as TEN, and between 10 and 3 0 % as overlap S J S - T E N . S e v e r a l studies of S J S h a v e b e e n reported A'orldwide*'*''''. However, there has b e e n no report of a Correspondence to: iingalavanija S. Dermatology Unit, Queen Sirikil National nstitule of Child Health. Bangkok 10400, Thailand, ^hone & Fax: 0-2354-8439 l-mail:srisupalak@yahoo. com

^ Med Assoc Thai Vol. 94 Suppl. 3 2011

large series of S J S in children. T h e authors r e v i e w e d the cases of S J S for 2 9 y e a r s at Q u e e n Sirikit N a t i o n a l Institute of Child Health w h i c h is the tertiary c h i l d r e n ' s hospital in B a n g k o k , T h a i l a n d . Material and Method A retrospective chart review w a s p e r f o r m e d on patients admitted to Q u e e n Sirikit National Institute of Child HeaUh or C h i l d r e n ' s Hospital. T h e clinical d i a g n o s i s of S J S w a s m a d e by d e r m a t o l o g i s t s . T h e patients should have at least t w o m u c o u s m e m b r a n e s i n v o l v e m e n t and epidermal a t t a c h m e n t less than 1 0 % body surface area involvement. Patients with a diagnosis of erythema multiforme or toxic epidermal necrolyis were excluded from the present study. T h e authors, collected data into three p h a s e s from 1979 to 1 9 8 7 , 1 9 8 8 to 1997 a n d from 1998 to 2 0 0 7 ( 2 9 year-study).

S85

T h e following data w e r e recorded: a g e , sex, d r u g s i n t a k e , e v i d e n c e of m y c o p l a s m a i n f e c t i o n , t r e a t m e n t s and c o m p l i c a t i o n s .

included non-steroid anti-inflammatory d r u g s 8 cases ( 5 % ) , antimalarial 4 cases ( 2 % ) , and unknown drugs 26 cases ( 1 6 % ) . T h e detailed list of d r u g s is shown in Table 2 and Fig. 1-3.

Results

For m y c o p l a s m a infection, the authors investigated in c a s e s that did not have a history of d r u g e x p o s u r e . Of this the authors found only 5 cases ( 3 % ) that the m y c o p l a s m a titer w a s positive in rising four fold titer.

A total of 189 patients w e r e admitted during this period. There were 5 6 cases between 1979-1987, 72 c a s e s b e t w e e n l 9 8 8 - 1 9 9 7 and 61 c a s e s b e t w e e n 1 9 9 8 2 0 0 7 . T h e r e w e r e 6-7 cases of S J S per year. T h e ratio between male to female w a s 1.6:1. T h e age ranged from 2 m o n t h s to 15 years with the m e a n age w a s 5.2 ± 3.6 years (Table 1). One hundred and sixty-five cases ( 8 7 % ) had a history of d r u g e x p o s u r e . T h e most c o m m o n d r u g e x p o s u r e w a s a n t i b i o t i c s in 6 9 c a s e s ( 4 2 % ) , a n t i c o n v u l s a n t d r u g s in 5 8 c a s e s ( 3 5 % ) . A m o n g the antibiotics group, penicillin groups (25%) and s u l f o n a m i d e g r o u p ( 1 2 % ) w e r e the m o s t c o m m o n m e d i c a t i o n s associated with S J S in all p h a s e s but the c e p h a l o s p o r i n g r o u p w a s the causative d r u g only in the last ten years ( 1 9 9 8 - 2 0 0 7 ) . A n t i c o n v u l s a n t s w e r e the s e c o n d c a u s e of S J S ( 3 5 % ) of w h i c h phenobarbital ( 1 6 % ) , c a r b a m a z e p i n e ( 1 5 % ) and phenytoin ( 4 % ) w e r e the c a u s a t i v e d r u g s r e s p e c t i v e l y . T h e o t h e r d r u g s

T r e a t m e n t of S J S varied b a s e d on time of a d m i s s i o n and extend of body surface involvement. All patients w e r e treated with cessation of causative d r u g s and supportive care that included aseptic skin c a r e , a d e q u a t e n u t r i t i o n a n d fluid m a n a g e m e n t . O p h t h a l m o l o g i s t s ' consultations w e r e performed in all c a s e s that had eye involvement. One hundred and nine cases (58%) were treated with systemic corticosteroids for 1-2 w e e k s . T h e corticosteroid treatment increased from 18% in the first phase to 6 4 % and 8 7 % in the second and third p h a s e , respectively. N o patients received intravenous i m m u n o g l o b u l i n . C o m p l i c a t i o n s of S J S in the present study w e r e found in 38 cases ( 2 0 % ) . Superimposed bacteria! skin infection w a s the most complication in 16

l ^ b l e 1. Demographic data of SJS patients in 3 phases

No of cases Mean age (years) Range Sex ratio (Male: female)

TBh\e2.

1979-1987

1988-1997

lW8-2nn7

Tola

56 4.7 ± 3.3 2 months-13 years 1.9: 1

72 5.3 ± 3.6 3 months-14 years 2: 1

61 5.6 ± 4.0 6 months-15 years 1: 1

189 5.2 ± 3.6 2 months-15 years 1.6: 1

Drug etiologies of SJS 1979-1987 (n = 56)

No of patients with drug exposure Antibiotics Penicillin Sulfonamide Cephalosporin Tetracycline Anticonvulsants Phenobarbital Carbamazepine Phenytoin Non-steroid anti-inflammatory drugs Antimalarial drugs Unknown drugs

S86

47 (84 % ) 18 (38%) 14 (30%) 3 (6%) 0 1 (2%) 10 (21%) 5 (11%) 3 (6%) 2 (4%) 3 (6%) 3 (6%) 14(29%)

1988-1997 (n = 72) 1998-2(K)7(n = 61)ToIal(n= 189) 67 (93 %) 22 (33%) 15 (23%) 7 (10%) 0 0 32 (48%) 17 (25%) 11 (17%) 4 (6%) 0 1 (1%) 12 (18%)

51 (84 %) 29 (57%) 12(24%) 10(19%) 7 (14%) 0 16(31%) 5 (10%) 11 (21%) 0 5 (10%) 0 0

165 (87%) 69 (42%) 41 (25%) 20(12%) 7 (4%) 1 (1%) 58 (35%) 27(16%) 25 (15%) 6 (4%) 8 (5%) 4 (2%) 26(16%)

J Med Assoc Thai Vol. 94 Suppl. 3 2011

cases (8%). Other comphcations were eye complications in 12 cases ( 6 % ) , hepatitis in 4 cases ( 2 % ) a n d other c o m p l i c a t i o n s in 6 c a s e s ( 2 % ) ( T a b l e 3 ) . E y e complications were keratitis in 4 cases, corneal ulcer in 2 cases, corneal abrasion in 2 cases, trichiasis in 1 case and blindness in 1 case (Table 4). T e n patients ( 5 % ) died from sepsis and underlying diseases. T h e mortality rate declined from 9 % from the first p h a s e to 1.5% in the third phase. Discussion

Similar to another report in A s i a n children, the authors found m a l e s to be m o r e p r e d o m i n a n t than females with the m e a n age of 5.2 + 3.6 years'^'. T h e etiology of S J S in the p r e s e n t study w a s s i m i l a r t o o t h e r s t u d i e s that d r u g s w e r e t h e m o s t c o m m o n etiology^^'^*. T h e m o s t c o m m o n d r u g s implicated in all p h a s e s w e r e antibiotics a n d anticonvulsants. T h e penicillin g r o u p and s u l f o n a m i d e group w e r e the most c o m m o n antibiotics in S J S patients. A m o n g anticonvulsants, besides phenobarbital and p h e n y t o i n , the authors found that c a r b a m a z e p i n e w a s

T h e present study w a s t h e largest study of SJS in children that had a long time case series. In the present study, there w e r e 6-7 cases of S J S p e r year.

25 20 • Phenobarbital

19 •Antfl)k>tlcs

• Carbamazepine

10

• AnUconvulsanls

5

a Norf-cterold antlInnammatWY drugs • Unknown drugs

0

I.

• Phenytoin

1979- 1988- 1998- Total 1987 1997 2007

Fig. 3 Drug etiology: anticonvulsants 1979-1987 1988-1997 1998-2007

Total

Fig. 1 Drug etiologies of Stevens-Johnson syndrome

a Cy* com(Mlcatk>ns

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• SultanamlM

•c«piuiosponn

1979-1987

1988-1997

199S-2D07

1979-1987 1988-1997 1998-2007

Fig. 2 Drug etiology: antibiotics

Total

Fig. 4 Serious comphcations of SJS

Table 3. Treatments and complications of SJS 1979-1987 (n - 5 6 ) No of corticosteroidtreatment Total complications Eye complications Skin infections Hepatitis Other complications

Death

10(18%) 11 (28%) 4 (7%) 3 (5%) 0 4 (7%)

5 (9%)


1988-1997 (n = 72) 46 (64%) 20 (43%) 6 (8%) 9 (12%) 3 (4%) 2 (2%) Renal failure 1 case (1%) GI hemorrhage 1 case (1 %) 4 (6%)

1998-2007 (n = 61) Total (n= 189) 53 (87%) 7(1%) 2 (3%) 4 (7%) 1 (1%) 0 1 (1.6%)

109 38 12 16 4

(58%) (20%) (6%) (8%) (2%)

6 (3%) 10 (5%)

587

Table 4. Eye complications of SJS Eye complications Corneal ulcer Trichiasis Blindness Keratitis Ectropion Corneal abrasion Total

1979-1987 (n = 56)

1988-1997 (n = 72)

2 (3.4%) 1 (1.7%) 1 (1.7%) 0 0 0 4 (7%) 0

the increasing i m p o r t a n t c a u s e of S J S especially in the third p h a s e . T h e other u n c o m m o n d r u g s w e r e n o n steroid anti-inflammatory drugs. Recently data s h o w e d t h a t g e n e t i c s s u s c e p t i b i l i t y p l a y e d a r o l e in t h e p a t h o g e n e s i s of S J S / T E N in A s i a n patients. C h u n g found s t r o n g association b e t w e e n H L A - B * 1 5 0 2 a n d carbamazepine induced SJS/TEN among Han Chinese''^'. In T h a i l a n d , L o c h a r e o n k u l found that the prevalence of H L A - B * 1502 in Thai patients w a s 9 % " " and found c a r b a m a z e p i n e induced S J S associated with H L A - B * 1502 allele in T h a i p o p u l a t i o n . In the future, g e n o t y p i n g for H L A - B * 1 5 0 2 m a y b e d o n e before treatment with c a r b a m e z e p i n e to d e c r e a s e the risk of SJS"^'. Beside the drug etiology of S J S , m y c o p l a s m a infection w a s a potentially c a u s e of S J S in children than in adult'"''. In the present study, the authors found m y c o p l a s m a infection in only 3% of cases. M a n a g e m e n t of S J S i n c l u d e s p r o m p t d i a g n o s i s and d i s c o n t i n u a t i o n of all suspected d r u g s . Early w i t h d r a w a l of the causative d r u g is associated with a better p r o g n o s i s ' I n f e c t i o u s c a u s e s s h o u l d b e s o u g h t and treated. S u p p o r t i v e treatment is very important*"* In S J S patients, special attention to fluid r e q u i r e m e n t s , electrolyte b a l a n c e , i n t r a v e n o u s caloric r e p l a c e m e n t , m e t i c u l o u s skin care and a v o i d a n c e of s e c o n d a r y infection are important. W h e n ocular i n v o l v e m e n t is present, o p h t h a l m o l o g i c consultation s h o u l d be o b t a i n e d . T h e r o l e o f s y s t e m i c c o r t i c o s t e r o i d is c o n t r o v e r s i a l b u t s h o r t t e r m a d m i n i s t r a t i o n of i n t r a v e n o u s s y s t e m i c c o r t i c o s t e r o i d is s o m e t i m e s a d v o c a t e d if it is started within the first 2-3 d a y s of a d r u g - i n d u c e d reaction'^-'. R i s k s of p r o l o n g e d use of s y s t e m i c c o r t i c o s t e r o i d are i n c r e a s i n g s e c o n d a r y infections, p r o l o n g e d w o u n d healing, m a s k i n g early s i g n s of s e p s i s and g a s t r o i n t e s t i n a l b l e e d i n g . I n t r a v e n o u s i m m u n o g l o b u l i n is a useful a n d safe therapy in severe c a s e s of S J S or T E N w h i c h d o not

S88

0 1 0 4 1 0 6

1998-2007 (n = ()l) 0 0 0 0 0 2 (3%) 2 (3%)

(1%) (6%) (1%) (8%)

Total (n = 189) 2 (0.01%) 2 (0.01%) 1 (0,05%) 4 (0.02%) 1 (0.005%) 2 (0.01%) 12(6%)

respond to s y s t e m i c corticosteroid""'. In the present study, the authors increased the use of systemic corticosteroid from 1 8 % in the first p h a s e to 6 4 % and 8 7 % in the second and third phase, respectively. T h e a u t h o r s ' experience of corticosteroid treatment in S J S s h o w s the a d v a n t a g e of decreasing the d u r a t i o n of the d i s e a s e and the s e r i o u s c o m p l i c a t i o n s such as eye c o m p l i c a t i o n as well as the mortality rate. In conclusion, etiology of SJS in Thai children w a s a s s o c i a t e d w i t h d r u g e x p o s u r e w i t h the most c o m m o n l y implicated drugs being antibiotics and anticonvulsants. Corticosteroid m a y have a role in the treatment of S J S . Potential conflicts o f interest None. References 1. R z a n y B, M o c k e n h a u p t M , Baur S, Schroder W, S t o c k e r U , M u e l l e r J, el al. E p i d e m i o l o g y of erythema exsudativum multiforme majus, StevensJohnson s y n d r o m e , and toxic epidermal necrolysis in G e r m a n y (1990-1992): structure and results of a population-based registry. J Clin Epidemiol 1996; 49:769-73. 2

Chan H L , Stern R S , A m d t K A , Langlois J, Jick SS, Jick H, et al. The incidence of erythema multiforme, S t e v e n s - J o h n s o n s y n d r o m e , and toxic epidermal n e c r o l y s i s . A p o p u l a t i o n - b a s e d study with particular r e f e r e n c e to r e a c t i o n s c a u s e d by d r u g s a m o n g outpatients. Arch Dermatol 1990; 126:43-7.

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10. Levi N, Bastuji-Garin S, Mockenhaupt M , Roujeau J C , Flahault A , Kelly JP, et al. M e d i c a t i o n s as risk factors of S t e v e n s - J o h n s o n s y n d r o m e and toxic epidermal necrolysis in children: a pooled a n a l y sis. Pediatrics 2009; 123: e297-304. 11. Arif H, B u c h s b a u m R, Weintraub D , K o y f m a n S, Salas-Humara C, Bazil C W , et al. C o m p a r i s o n and predictors of rash associated w i t h 15 antiepileptic drugs. Neurology 2007; 6 8 : 1 7 0 1 - 9 . 12. Roujeau J C , Kelly JP, Naldi L, R z a n y B , Stern R S , A n d e r s o n T, et al. M e d i c a t i o n use a n d the risk of S t e v e n s - J o h n s o n s y n d r o m e or t o x i c e p i d e r m a l necrolysis. N Engl J M e d 1995; 3 3 3 : 1 6 0 0 - 7 . 13. H u n g SI, C h u n g W H , Jee S H , C h e n W C , C h a n g Y T , L e e W R , et al. G e n e t i c s u s c e p t i b i l i t y to c a r b a m a z e p i n e - i n d u c e d c u t a n e o u s a d v e r s e drug reactions. Pharmacogenet Genomics 2006; 1 6 : 2 9 7 306. 14. C h u n g W H , H u n g SI, H o n g H S , H s i h M S , Yang L C , H o H C , et al. Medical genetics: a m a r k e r for

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21.

Ghislain P D , Roujeau J C . Treatment of severe drug r e a c t i o n s : S t e v e n s - J o h n s o n s y n d r o m e , toxic e p i d e r m a l necrolysis a n d hypersensitivity s y n d r o m e . Dermatol Online J 2002; 8 : 5 .

22. M a r t i n e z A E , A t h e r t o n DJ. H i g h - d o s e s y s t e m i c c o r t i c o s t e r o i d s can arrest r e c u r r e n c e s of s e v e r e mucocutaneous erythema multiforme. Pediatr Dermatol 2000; 17:87-90. 23. Schneck J, Fagot JP, Sekula P, Sassolas B , Roujeau J C , M o c k e n h a u p t M. Effects of t r e a t m e n t s o n the mortality of S t e v e n s - J o h n s o n s y n d r o m e a n d toxic e p i d e r m a l n e c r o l y s i s : A r e t r o s p e c t i v e study on patients i n c l u d e d in the p r o s p e c t i v e E u r o S C A R Study. J A m A c a d Dermatol 2 0 0 8 ; 5 8 : 3 3 - 4 0 . 24. Yang Y, X u J, Li F, Zhu X. C o m b i n a t i o n therapy of intravenous i m m u n o g l o b u l i n a n d corticosteroid in the treatment of toxic e p i d e r m a l n e c r o l y s i s and S t e v e n s - J o h n s o n s y n d r o m e : a retrospective c o m parative study in C h i n a . Int J D e r m a t o l 2 0 0 9 ; 4 8 : 1122-8.

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