|Year : 2018 | Volume
| Issue : 1 | Page : 9-14
Stevens-Johnson syndrome and toxic epidermal necrolysis in children
Sudip Das1, Ramkumar Ramamoorthy2
1 Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
2 Department of Dermatology, Kanchi Kamakoti Child Trust Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||28-Dec-2017|
Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
SJS and TEN are diseases characterised by epidermal detachment and necrolysis predominantly of drug induced etiology. SJS/TEN begins with a prodrome of fever, malaise, anorexia, pharyngitis, and headache lasting for 2-3 days, at times, extending to 10-11 days. Mucosal lesions usually precede skin lesion. Usually, two mucosal membranes are involved, most commonly conjunctiva and oral mucosa. Oral mucosal involvement is seen in 90% of SJS and almost all patients diagnosed with TEN. In SJS, mucosal involvement is widespread and confl uent in contrast to erythema multiforme where it is focal and seen in only 25%-60% of cases. The exact pathogenesis of SJS and TEN is not fully elucidated. In view of the paucity of T-cell infiltrate,keratinocyte apoptosis could be the result of autocrine or paracrine interaction between Fas, a death receptoron keratinocyte and Fas Ligand (FasL) produced by the keratinocytes along with the substantial contributionof soluble FasL from peripheral mononuclear cells. FasL upregulation in keratinocytes is nitric oxide-dependent anddriven by T-cell derived tumor necrosis factor (TNF) alpha and Interferon-gamma.The management revplves around immediate stoppage of drug and.,supportive care .IVIG,corticosteroids and cyclosporine are all effective drugs but no RCT is available for any of them
Keywords: Children, Stevens-Johnson syndrome, toxic epidermal necrolysis
|How to cite this article:|
Das S, Ramamoorthy R. Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Indian J Paediatr Dermatol 2018;19:9-14
|How to cite this URL:|
Das S, Ramamoorthy R. Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Indian J Paediatr Dermatol [serial online] 2018 [cited 2019 Jul 22];19:9-14. Available from: http://www.ijpd.in/text.asp?2018/19/1/9/221775
| Introduction|| |
Stevens-Johnson syndrome More Details (SJS) was first described by the two pediatricians (A. M. Stevens and F. C. Johnson) in 1922 in the New York city in two children in whom the illness was most likely triggered by infection. In 1956, A. Lyell used the term toxic epidermal necrolysis (TEN) to describe the chafed-looking skin lesions in four of his patients, based on the belief that these lesions were induced by a circulating toxin. TEN was also independently described by Lang and Walker in 1956.
| Definition|| |
SJS and TEN are considered to be variants of the same pathologic process. A classification scheme based on the severity of epidermal detachment at the worst stage of the disease was described by Bastuji-Garin et al. The following categories are included:
- Bullous erythema multiforme - Localized “typical targets” or “raised atypical target lesions” with epidermal detachment below 10% of body surface area (BSA)
- SJS - detachment below 10% of BSA plus widespread erythematous or purpuric macules or flat atypical target lesion in addition to blisters and erosions in 1 or more mucous membranes
- Overlap SJS-TEN - detachment between 10% and 30% of BSA plus widespread erythematous or purpuric macules or atypical target-like annular patches
- TEN with spots-detachment of above 30% of BSA plus widespread purpuric macules or atypical target lesions and
- TEN without spots-detachment in large epidermal sheets and above 10% of BSA without purpuric macules or target lesions.
Raised atypical target lesions (ill-defined, round palpable lesions with only two zones (central raised edematous area with an erythematous border) should be differentiated from target lesions which are round, sharply demarcated lesions comprising three zones [Figure 1]. Flat atypical target lesions-ill-defined, with only two nonpalpable zones, central may be blistered [Figure 2].
| Clinical Features|| |
SJS/TEN begins with a prodrome of fever, malaise, anorexia, pharyngitis, and headache lasting for 2–3 days, at times, extending to 10–11 days. Mucosal lesions usually precede skin lesions. Usually, two mucosal membranes are involved, most commonly conjunctiva and oral mucosa.
Oral lesions occur in crops. Thickly walled vesicles rupture into irregularly shaped ulcers covered by pseudomembranes are seen in lips, buccal mucosa, palate, the anterior, and lateral border of the tongue. Gums are spared in contrast to herpetic gingivostomatitis. Oral mucosal involvement is seen in 90% of SJS and almost all patients diagnosed with TEN. In SJS, mucosal involvement is widespread and confluent in contrast to erythema multiforme where it is focal and seen in only 25%–60% of cases.
Skin lesions are accompanied by pain, which is a characteristic feature of SJS and TEN. Flat atypical target lesions or erythematous macules of irregular shape and size with are seen. Skin lesions are seen initially on the face, neck, chest, trunk, and proximal extremities. This is followed by confluence and development of flaccid blisters. SJS should be differentiated from erythema multiforme major which is recognized by the presence of acrally distributed typical target lesions, and are not associated with significant skin detachment.
Early detection of pulmonary complications requires a high degree of clinical suspicion. Children may present with dyspnea, bronchial hypersecretion, hypoxemia, and sloughing of the bronchial mucosa are seen in the acute stage of the illness. Chest radiography may not show any abnormality or may reveal interstitial infiltrates. Delayed complications include pneumonitis, atelectasis, and pneumothorax.
Other complications of SJS and TEN include microalbuminuria and presence of renal tubular enzymes in urine, arthralgia, hepatitis, encephalopathy, and myocarditis.
| Etiology|| |
SJS is very rarely seen in very young children. This may also be due to less possibility for exposure to potentially sensitizing drugs in this age group. However, the incidence of skin reaction to lamotrigine in children is 1:100, comparatively much higher than the reported incidence of 1:1000 in adults. Concomitant administration of valproic acid and faster dose escalation are the risk factors for developing adverse drug reaction to lamotrigine.,
Drugs are implicated in the majority of adults and children with SJS or TEN. A thorough search for the intake of drugs within 8 weeks before the onset of the rash is mandatory. Common drugs that are known to cause pediatric SJS and TEN are included in [Table 1]. It is noteworthy that antibiotics are a leading cause of drug-induced SJS in children, whereas allopurinol, nevirapine, and piroxicam are uncommon causes. However, infections could play a major role in triggering SJS in children, outnumbering drug-induced cases in some studies. Mycoplasma pneumonia is implicated as an etiological factor in SJS, especially in children who present with mucosal lesions and limited skin involvement. Pulmonary involvement is a common associated feature in mycoplasma pneumonia triggered SJS or TEN. Other triggers include herpes simplex virus, streptococci, cytomegalovirus, live virus vaccinations, and DPT vaccination.
|Table 1: Drugs causing Stevens-Johnson syndrome and toxic epidermal necrolysis in children|
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| Pathophysiology|| |
The exact pathogenesis of SJS and TEN is not fully elucidated. In view of the paucity of T-cell infiltrate, keratinocyte apoptosis could be the result of autocrine or paracrine interaction between Fas, a death receptor on keratinocyte and Fas Ligand (FasL) produced by the keratinocytes  along with the substantial contribution of soluble FasL from peripheral mononuclear cells. FasL upregulation in keratinocytes is nitric oxide-dependent and driven by T-cell derived tumor necrosis factor (TNF) alpha and Interferon-gamma.
Drug-specific CD8+ cytotoxic T-cells release perforins and granzyme on direct contact with keratinocytes expressing specific MHC alleles is also a possible mechanism for the development of drug-induced SJS and TEN. Many publications have confirmed the strong association between Carbamazepine-induced SJS and HLA-B*15:02 as well as HLA-B*57:01and abacavir hypersensitivity. The predictive value testing of HLA-B*15:02 in Indian population is supported by two recently conducted studies. The positive predictive value of the presence of HLA-B*15:02 in predicting SJS/TEN following usage of carbamazepine ranges from 3% to 7.7%.
An overwhelming body of evidence points out to the role of granulysin in the pathogenesis of SJS and TEN. Granulysin is a protein expressed in two isoforms (15 KDa and 9 KDa), produced by CD8+ Cytotoxic T-cells, natural killer T-cells and natural killer cells. Granulysin is detected at much higher levels in blister fluid of TEN than FasL, granzyme, and perforin. High serum levels of granulysin were found in SJS and TEN 2–4 days before the development of skin lesions. This is in contrast to the declining levels of soluble FasL about 3–6 days following clinical course of SJS and TEN. Soluble FasL is secreted by monocytes and keratinocytes and increases before the development of skin lesions. Moreover, FasL was found to elevated in patients diagnosed with the drug-induced maculopapular exanthematous eruption.
Keratinocyte apoptosis can also be mediated by annexin-1 receptor on monocytes interacting with formyl peptide receptor 1 on keratinocytes leading to necroptosis, a form of cell death.
High mobility group B protein (HMGB1) is considered to play a central role in the pathogenesis of SJS and TEN. This protein functions as a transcription factor intracellularly and as an activator of inflammatory cascade extracellularly. HMGB1 levels can be estimated by means of an immune assay, and it remains elevated for a longer time than granulysin.
Interleukin 15 (IL-15) levels correlated with disease progression and mortality associated with SJS and TEN. IL-15 may play a pivotal role in the pathogenesis of SJS and TEN. IL-15 induces the expression of granulysin and enhances the activity of NK cell and CD8+ cytotoxic T-cells.
| Diagnosis|| |
The diagnosis of SJS and TEN is based on clinical findings. Histopathology is not specific [Figure 1]. Skin biopsy and immunofluorescence may be required in special situations to rule other diseases which have a similar clinical presentation [Table 2]. Investigation for coexistent drug rash with eosinophilia and systemic symptoms is recommended.
|Table 2: Differential diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis|
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| Prognosis|| |
Score of ten (SCORETEN) is a severity of illness score specific for SJS and TEN [Table 3]. It is a useful tool for predicting the mortality and is calculated on day 1 and day 3 of the illness. The usefulness of SCORTEN in childhood SJS and TEN has been validated in a recently published study.
In general, the mortality of SJS is <5%, whereas around 30% of patients diagnosed with TEN die during the acute stage of the illness.
| Management|| |
Early withdrawal of the offending drug and is found to improve the overall prognosis. This is especially in SJS/TEN triggered by drugs which have a short elimination half-life. Concomitant administration of medications known to decrease the elimination of the offending drug should be discontinued.
Supportive care forms the cornerstone of therapy. In SJS and TEN, superior results were obtained by supportive care alone compared to administration of glucocorticoids or Intravenous immunoglobulin (IVIG), in reducing the associated mortality. Early referral of the child to the intensive care unit or to a center specialized in caring for burns is required. Children may refuse to void due to pain resulting from urethritis or balanitis or vulvovaginitis, requiring the need for catheterization. Feeding by nasogastric tube is often required. Careful adherence to oral hygiene is needed to avoid superinfection.
Nutritional requirements of the child are to adequately taken care off. The following formula is useful in calculating the daily energy requirements of a child with SJS or TEN. Energy requirements (in calories) for pediatric SJS/TEN patients is estimated by the following equation.
Daily requirement in calories = (preinjury weight [kg] × 9 24.6) + (wound size [% of BSA] ×4.1) +940 calories.
Fluid requirements are about 30% lower than that required for patients with burns.
| Care of the Skin|| |
Extensive debridement is not advisable in children. The detached epidermis can be left over and would often serve as a biological dressing. In children who have extensive skin necrosis, gentle cleansing followed by biological dressing is recommended. Maintaining room temperature at 30°C–32°C is recommended in addition to strict aseptic precautions, maintenance of fluid, acid-base and electrolyte balance.
Swabs for bacterial culture and sensitivity should be performed at regular intervals (preferably once in every 3rd day) along with periodic blood culture. Staphylococcus aureus is the commonest cause of superinfection in early stage followed by Pseudomonas aeruginosa the late stages of SJS. The negative predictive value of skin cultures for sepsis has been emphasized in a recently published work by de Prost et al.
| Care of the Genitalia|| |
Daily inspection of genitalia is needed during the acute stage of the illness. Vaginal synechiae, and vaginal adenosis are among the well-known complications of SJS and TEN. Vulval erosions can be treated with judicious usage of topical steroids belonging to group three of the potency chart for topical steroids (fluticasone propionate ointment, betamethasone valerate 0.1% or betamethasone dipropionate 0.05%). Menstrual suppression is a yet another option which can be considered in female adolescents. Urethral metal stenosis is a long-term genital complications in male children.
| Care of the Eyes|| |
Immediate consultation with ophthalmologist is mandatory in a child diagnosed with SJS or TEN. The ocular complications of SJS and TEN may either accompany or follow the skin lesions. Ocular involvement is reported in 75% of cases.
Ophthalmological follow-up during acute phase of the disease is also recommended. Ocular complications include mucopurulent conjunctivitis in the acute stage followed by long-term complications such as dry eye, synechiae, symblepharon, and trichiasis. Visual loss secondary to corneal scarring and vascularization is the most dreaded long-term ocular complication of SJS and TEN. Eye care includes the use of preservative-free lubricant eye drops, daily removal of pseudomembranes, daily breaking of synechiae, topical corticosteroids, and laser hair removal for trichiasis.
| Systemic Therapy|| |
Corticosteroids, IVIG, cyclosporin, TNF blockers have all been used in the management of SJS and TEN., None of them have been tested by randomized control trials. The severity and rarity of the condition precludes the possibility of conducting randomized controlled trials in this disorder. Based on the published studies, no definite conclusion could be made regarding the efficacy of systemic steroids in reducing the mortality and morbidity of SJS and TEN.
IVIG should be administered early in the course of the illness, preferably within 48 h of onset of clinical disease  at a total dose of 3 g/kg over a period of 3–5 days. Kim et al. noticed improvement in ocular outcome, if IVIG is given within 6 days of disease onset. Similarly, good results in ocular complications were obtained if systemic steroids were instituted within 6 days of symptom onset. However, neither IVIG nor steroids influenced the overall mortality rate of SJS or TEN based on SCOTEN scoring. A tendency toward reduction in recovery time following usage of a combination of IVIG with systemic steroids was observed in a recently published meta-analysis. Cyclosporine is given at 3–6 mg/kg for 1 week followed by a tapering course. In a retrospective study, cyclosporine gave superior results in terms of improvement in mortality when compared to IVIG. However, the results could be confounded by the fact that the group of patients who received cyclosporine were relatively more healthy. A recent meta-analysis comparing cyclosporine with other immunomodulators showed a consistent effect of cyclosporine on the reduction of mortality associated with SJS and TEN.
| Conclusion|| |
Childhood SJS and TEN are diseases associated with high mortality and significant long-term morbidity. Early diagnosis, immediate referral to an intensive care center for supportive care and dedicated effort by a multidisciplinary team of experts form the pillars of treatment. In resource-poor setting, corticosteroids started earlier are a good alternative to both cyclosporine and IVIG.
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| References|| |
Callahan SW, Oza VS. Stevens-Johnson syndrome – A look back. JAMA Dermatol 2017;153:240.
Ringheanu M, Laude TA. Toxic epidermal necrolysis in children – An update. Clin Pediatr (Phila) 2000;39:687-94.
Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC,et al
. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92-6.
Levi N, Bastuji-Garin S, Mockenhaupt M, Roujeau JC, Flahault A, Kelly JP,et al
. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: A pooled analysis. Pediatrics 2009;123:e297-304.
Creamer D, Walsh SA, Dziewulski P, Exton LS, Lee HY, Dart JK,et al
. U.K. Guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol 2016;174:1194-227.
Schneider JA, Cohen PR. Stevens-Johnson syndrome and toxic epidermal necrolysis: A concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther 2017;34:1235-44.
Nakajima S, Watanabe H, Tohyama M, Sugita K, Iijima M, Hashimoto K,et al
. High-mobility group box 1 protein (HMGB1) as a novel diagnostic tool for toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol 2011;147:1110-2.
Ferrandiz-Pulido C, Garcia-Patos V. A review of causes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Arch Dis Child 2013;98:998-1003.
Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H,et al
. Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble fas ligand. Am J Pathol 2003;162:1515-20.
Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS,et al
. Stevens-Johnson syndrome and toxic epidermal necrolysis: A review of the literature. Ann Allergy Asthma Immunol 2005;94:419-36.
Khor AH, Lim KS, Tan CT, Wong SM, Ng CC. HLA-B*15:02 association with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in an Indian population: A pooled-data analysis and meta-analysis. Epilepsia 2014;55:e120-4.
Léauté-Labrèze C, Lamireau T, Chawki D, Maleville J, Taïeb A. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 2000;83:347-52.
Kinoshita Y, Saeki H. A review of the pathogenesis of toxic epidermal necrolysis. J Nippon Med Sch 2016;83:216-22.
Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY,et al
. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008;14:1343-50.
Thong BY. Stevens-Johnson syndrome/toxic epidermal necrolysis: An Asia-pacific perspective. Asia Pac Allergy 2013;3:215-23.
Saito N, Qiao H, Yanagi T, Shinkuma S, Nishimura K, Suto A,et al
. An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions. Sci Transl Med 2014;6:245ra95.
Su SC, Mockenhaupt M, Wolkenstein P, Dunant A, Le Gouvello S, Chen CB,et al
. Interleukin-15 is associated with severity and mortality in Stevens-Johnson syndrome/Toxic epidermal necrolysis. J Invest Dermatol 2017;137:1065-73.
Gupta LK, Merlin AM, Agarwal N, Dsouza P, Das S, Kumar R,et al
. Guidelines for management of Steven Johnson syndrome/toxic epidermal necrolysis. An Indian perspective. Indian J Dermatol Venerol Leprol 2016;82:603-25.
Roujeau JC. Epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis): Historical considerations. Dermatol Sin 2013;30:169-74.
Beck A, Quirke KP, Gamelli RL, Mosier MJ. Pediatric toxic epidermal necrolysis: Using SCORTEN and predictive models to predict morbidity when a focus on mortality is not enough. J Burn Care Res 2015;36:167-77.
Guégan S, Bastuji-Garin S, Poszepczynska-Guigné E, Roujeau JC, Revuz J. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol 2006;126:272-6.
Mayes T, Gottschlich M, Khoury J, Warner P, Kagan R. Energy requirements of pediatric patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Nutr Clin Pract 2008;23:547-50.
de Prost N, Ingen-Housz-Oro S, Duong Ta, Valeyrie-Allanore L, Legrand P, Wolkenstein P,et al
. Bacteremia in Stevens-Johnson syndrome and toxic epidermal necrolysis: Epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore) 2010;89:28-36.
Kaser DJ, Reichman DE, Laufer MR. Prevention of vulvovaginal sequelae in Stevens-Johnson syndrome and toxic epidermal necrolysis. Rev Obstet Gynecol 2011;4:81-5.
Gueudry J, Roujeau JC, Binaghi M, Soubrane G, Muraine M. Risk factors for the development of ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2009;145:157-62.
Lehman SS. Long-term ocular complication of Stevens-Johnson syndrome. Clin Pediatr (Phila) 1999;38:425-7.
Gürcan HM, Ahmed AR. Efficacy of various intravenous immunoglobulin therapy protocols in autoimmune and chronic inflammatory disorders. Ann Pharmacother 2007;41:812-23.
Enk AH, Hadaschik EN, Eming R, Fierlbeck G, French LE, Girolomoni G,et al
. European guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology. J Eur Acad Dermatol Venereol 2016;30:1657-69.
Ye LP, Zhang C, Zhu QX. The effect of intravenous immunoglobulin combined with corticosteroid on the progression of Stevens-Johnson syndrome and toxic epidermal necrolysis: A Meta-analysis. PLoS One 2016;11:e0167120.
Kim KH, Park SW, Kim MK, Wee WR. Effect of age and early intervention with a systemic steroid, intravenous immunoglobulin or amniotic membrane transplantation on the ocular outcomes of patients with Stevens-Johnson syndrome. Korean J Ophthalmol 2013;27:331-40.
Law EH, Leung M. Corticosteroids in Stevens-Johnson syndrome/toxic epidermal necrolysis: Current evidence and implications for future research. Ann Pharmacother 2015;49:335-42.
Kirchhof MG, Miliszewski MA, Sikora S, Papp A, Dutz JP. Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol 2014;71:941-7.
Valeyrie-Allanore L, Wolkenstein P, Brochard L, Ortonne N, Maître B, Revuz J,et al
. Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 2010;163:847-53.
González-Herrada C, Rodríguez-Martín S, Cachafeiro L, Lerma V, González O, Lorente JA,et al
. Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: Evidence from three different approaches. J Invest Dermatol 2017;137:2092-100.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]