Pediatric Annals

CME Article 

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

James Treat, MD

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening necrotic skin reactions caused by either medication or, less commonly, infection. SJS is characterized by acute epidermal necrosis of skin and mucous membranes involving less than 10% of the body surface area (BSA). If greater than 30% BSA involvement develops, the condition is termed TEN, a condition with a higher risk of mortality. If necrosis is between 10% and 30%, the reaction is often termed SJS-TEN overlap.1 Most authorities agree that SJS and TEN are on a spectrum, with TEN representing the worse end. In contrast, erythema multiforme (EM) is often a reaction to herpes simplex virus, is usually acrally located, does not have as prominent mucosal involvement or widespread erosions, and is typically not life-threatening. Therefore, although some believe EM lies on the spectrum with SJS and TEN, it is likely a separate entity.

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening necrotic skin reactions caused by either medication or, less commonly, infection. SJS is characterized by acute epidermal necrosis of skin and mucous membranes involving less than 10% of the body surface area (BSA). If greater than 30% BSA involvement develops, the condition is termed TEN, a condition with a higher risk of mortality. If necrosis is between 10% and 30%, the reaction is often termed SJS-TEN overlap.1 Most authorities agree that SJS and TEN are on a spectrum, with TEN representing the worse end. In contrast, erythema multiforme (EM) is often a reaction to herpes simplex virus, is usually acrally located, does not have as prominent mucosal involvement or widespread erosions, and is typically not life-threatening. Therefore, although some believe EM lies on the spectrum with SJS and TEN, it is likely a separate entity.

James Treat, MD, is Assistant Professor of Pediatrics and Dermatology, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia.

Dr. Treat has disclosed no relevant financial relationships.

Address correspondence to: James Treat, MD, is Assistant Professor of Pediatrics and Dermatology, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, 3550 Market Street, 2nd Floor Dermatology, Philadelphia, PA 19104; fax: 215-590-4948; e-mail: treat@email.chop.edu.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening necrotic skin reactions caused by either medication or, less commonly, infection. SJS is characterized by acute epidermal necrosis of skin and mucous membranes involving less than 10% of the body surface area (BSA). If greater than 30% BSA involvement develops, the condition is termed TEN, a condition with a higher risk of mortality. If necrosis is between 10% and 30%, the reaction is often termed SJS-TEN overlap.1 Most authorities agree that SJS and TEN are on a spectrum, with TEN representing the worse end. In contrast, erythema multiforme (EM) is often a reaction to herpes simplex virus, is usually acrally located, does not have as prominent mucosal involvement or widespread erosions, and is typically not life-threatening. Therefore, although some believe EM lies on the spectrum with SJS and TEN, it is likely a separate entity.

SJS and TEN are rare diseases (estimated at approximately 0.4 to 1.2 cases per million),2,3 and a genetic predisposition exists in at least some patients.4–6 Prompt diagnosis of SJS and TEN is extremely important as the disease can lead to great morbidity (dehydration, infection, loss of vision, strictures) and mortality (less than 5% with SJS up to 30% with TEN).3

Causes

SJS is usually caused by medications, and TEN is nearly exclusively caused by medications. There is a small list of medications that are the most common causes of SJS and TEN (see Table); there are other medications that have been implicated less often. The most common offenders are antibiotics (sulfonamides, fluoroquinolones, minocycline, cephalosporins and penicillins), anticonvulsants (lamotrigine, carbamazepine, phenytoin, phenobarbital), allopurinol, some non-steroidal anti-inflammatory drugs (NSAIDs), nevirapine, and sertraline.7 When a known, high-risk medication has been recently introduced, and there is a rash, especially with mucosal involvement and constitutional symptoms, SJS or early TEN should be highly suspected.

Common Medication Causes of SJS/TEN

Table 1: Common Medication Causes of SJS/TEN

Recently, certain HLA subtypes have been linked to a higher risk of SJS or a higher risk of complications with certain medications. The risk of SJS is so high in people who are HLA B*1502 positive and who take carbamazepine that the Food and Drug Administration (FDA) has issued a recommendation that HLA subtyping be done before prescribing carbamazepine in populations where this HLA subtype is very prevalent.8 Generally, the highest prevalence of HLA B*1502 is in Asian and South Asian Indian populations.4 Carbamazepine, oxcarbazepine, phenobarbital, and phenytoin are all aromatic anticonvulsants and, thus, patients allergic to one may be allergic to all of them. HLAB* 5901 and HLA-A*0206 have been associated with SJS with ocular complications in Japanese populations.5,6 There are other HLA subtype SJS associations whose links may become better recognized, and advances pharmacogenomics will hopefully help physicians lessen the risk of SJS in the future.

Aside from medications, no clear cause can be found, so there may be other infectious agents, which can induce SJS or TEN. The most well-established cause of SJS is mycoplasma infection.9 Because mycoplasma often affects children and young adults, SJS from mycoplasma is seen more commonly in this population (see Figure 1, page 669). Mycoplasma may cause very typical SJS or a variant, which is mucosal predominant with very little, if any, cutaneous involvement. This was originally described as severe mucositis, but clinically the acute reaction with full thickness necrosis is identical to SJS in the mouth and is caused by the same pathogen. Therefore, this mucosal predominant variant is likely on the spectrum of SJS.10,11 It is not known whether treatment of the mycoplasma with antibiotics shortens the course of SJS. There are reports of successful use of IVIg for mycoplasma-induced SJS (discussed later in this article).12

Necrosis of Mucosal Surface of Lips in Mycoplasma-Induced SJS. Figures Courtesy Mary Wu Chang.

Figure 1. Necrosis of Mucosal Surface of Lips in Mycoplasma-Induced SJS. Figures Courtesy Mary Wu Chang.

Herpes simplex has been reported as a cause of SJS, but many believe that the erythema multiforme (EM) reaction, which is often caused by herpes simplex, is not on the continuum with SJS.13 Localized, recurrent EM from herpes simplex infection has been termed herpes associated erythema multiforme (HAEM) and is somewhat different from SJS. The lesions of HAEM tend to be acral, very typical, round, uniform targets, and the mucosal involvement is not as exuberant or widespread.

There have been many other infectious diseases that have been postulated to be causal in SJS, but these are generally based on individual case reports, and additional studies are needed.

Pathophysiology

Various mechanisms for SJS have been proposed, including buildup of a toxic metabolite from a medication, or induction of apoptosis.14 TEN was first proposed by Viard et al. to be caused by an interaction between Fas Ligand (FasL) and Fas (CD95) leading to keratinocyte apoptosis.15 Fas is a receptor that is expressed on keratinocytes, and when it interacts with soluble FasL, it leads to keratinocyte apoptosis. Levels of FasL are very elevated in patients with TEN in contrast to patients with typical morbilliform drug eruptions. IVIg has been shown to be able to block the binding of Fas to FasL, thus explaining why it may be effective in SJS and TEN.15

Clinical Differential Diagnosis

Herpes Simplex Infection

Primary herpetic gingivostomatitis can mimic SJS due to the exuberant vesicles, erosions, and crusting in the mouth and on the lips but lacks the targetoid skin lesions. Recurrent herpetic infection are much less exuberant due to the buildup of immunity.

Staphylococcal Scalded Skin Syndrome

Staphylococcal scalded skin syndrome (SSSS) often presents with widespread erythema, desquamation, and superficial erosion especially concentrated in the intertriginous and perioroficial areas. A toxin secreted by Staphylococcus aureus causes SSSS. The toxin cleaves desmoglein 1 (DSG1), which helps with intracellular keratinocyte adhesion. This leads to sloughing and erosions. DSG3 serves a similar function to DSG1, is not targeted by the staphylococcal toxin, and is present in higher amounts in the mucosa. DSG3 protects the mucosa from blistering and sloughing in SSSS. Therefore, the lack of mucosal involvement is the key to differentiating SSSS from SJS.

Kawasaki Disease

Kawasaki disease (KD) can present with targetoid skin lesions with dry, red lips and red eyes. The mucosa are not necrotic and neither are the skin lesions and, therefore, the lack of blistering and erosions in KD differentiates it from SJS.

Urticaria

Urticaria (especially if annular and florid) can be mistaken for targetoid lesions. But urticaria should be itchy and not painful, the lesions move around, the patients are dermatographic, and there is no mucosal involvement. Urticaria usually responds well to oral antihistamines.

Pemphigus

Pemphigus vulgaris (PV) or paraneoplastic pemphigus (PNP) can cause crusted lips with bullae on the skin but is often more of an indolent course. PV may not be as confluent on the lips.

Diagnosis

The skin changes of SJS and TEN are often preceded by 1 to 7 days of low-grade fever, sore throat, or malaise. The systemic symptoms with fever are useful signs to help alert the clinician that the rash is not a typical, self-limited, medication eruption. The characteristic skin lesions of SJS and early TEN are targetoid with dusky/purple areas or frank vesiculation in the center (see Figure 2, page 669). The individual lesions may be irregular, and broad areas of purple necrotic skin are more widespread with severe disease. The skin lesions rapidly progress to blistering, sloughing, and result in widespread erosions. This transition may happen over hours to days. The dusky color of the patches and the blistering results from dying (necrotic) keratinocytes skin. Thus, an important differentiator in the diagnosis of SJS and TEN is the non-blanchable, non-mobile and painful nature of the skin lesions.

Purple Macules and Vesicles on Arm in Early TEN.

Figure 2. Purple Macules and Vesicles on Arm in Early TEN.

Necrotic mucosal lesions are necessary for and typically, the most striking feature, of SJS and TEN. Painful sloughing or crusting of the lips is often accompanied by intraoral erosions, is typically present very early in the progression of the skin disease, and may precede the targets. Ulcerations may extend into the esophagus and upper airway, thereby limiting the ability to eat. Exudative necrotic epithelium may compromise the airway. Attempts to insert either or nasogastric tube or intubate should be done very carefully due to the risk of introducing exudative necrotic epithelium into the airway.

The ocular mucosa are also often involved with conjunctival injection, sometimes progressing to pseudomembranes and synechiae. Synechiae are adherent connections between the iris and the cornea that must be broken urgently by an ophthalmologist to prevent permanent corneal scarring.

Erosions can occur in any other mucous membrane as well. Urethral involvement often presents as dysuria and scarring can occur. Vaginal involvement can also progress from painful erosions to scarring of the introitus. Any early adhesions should cleaved to prevent future dysparunia.

SJS is typically diagnosed clinically based upon recent exposure to a highrisk medication or mycoplasma infection, along with targetoid skin lesions with central necrosis and mucosal involvement. The diagnosis can be solidified with a few simple measures. An area of sloughed skin can be evaluated with frozen sections by an experienced pathologist to see if the necrosis involves the full thickness of the epidermis. This can also be done with a formal skin biopsy either rapidly with frozen sections or more slowly with formalin fixed sections. If there is only partial thickness epidermal necrosis, SSSS is more likely. An ophthalmologist can also play a key role diagnostically to help differentiate early involvement with SJS from a viral conjunctivitis or other inflammation.

Management and Therapeutics

Management of SJS and TEN involves identifying the cause (with discontinuation of the offending drug), halting the reaction if possible, and intensive supportive care. Due to its rarity, there are no large scale randomized placebo controlled trials for therapy of SJS or TEN. Therapeutic recommendations are off-label and based on in vitro data and case series. SJS and TEN are managed somewhat differently from a severe burn. Burn centers provide excellent wound care for widespread blistering. Clinicians must also be aware of the risk of systemic and mucous membrane involvement, (including ophthalmologic) as well as the unpredictable possibility of further progression. Therefore, transfer to a burn center must be accompanied by consultation with physicians experienced in managing SJS and TEN.

Systemic corticosteroids are controversial in their use in SJS and TEN as they increase the risk of sepsis and may increase the risk of death in TEN.16,17 This is likely caused by the immunosuppressing action of corticosteroids that can lead to infection, especially in the setting of widespread erosions upper airway erosions. Most mortality in SJS and TEN is related to sepsis and pulmonary infections.17 There is growing evidence for intravenous immunoglobulin for both medication induced and mycoplasma induced SJS/TEN.12,18 IVIg may be able to block the Fas-Fas Ligand interaction and therefore theoretically can halt keratinocyte apoptosis. It is vital that therapy is started as soon as possible because cell death cannot be reversed and any areas of full thickness necrosis will go on to blistering and sloughing. The typical dosing is 2 to 3 g/kg given in divided doses over 2 to 4 days.18

Proper follow-up with a dermatologist or wound care specialist is vital to monitor for skin infections and aid in healing. There are many wound care preparations, but care should be taken with applying any topical therapy over broad areas of eroded skin due to risk of absorption. For instance, silver sulfadiazine, which is often used in burn patients, has a sulfa moiety that may worsen SJS (if the patient is allergic to sulfa (see Figure 3, page 670) or even worse if the SJS was caused by a sulfa). Silver sulfadiazine can also rarely lead to bone marrow suppression or localized arygyria if over used.19 Bland emollients, such as petrolatum gauze, provide a barrier and moisturizing layer to help with reepithelialization. Topical antibiotics may be useful in areas that have high risk of superinfection, such as perioroficial and intertriginous areas.

An 18-Year-Old Female Developed SJS/TEN During Treatment with TMP/Sulfa. Widespread Painful, Purpuric Patches Developed on the Trunk and Extremities. Soon After, Bullae Developed from Necrosis and Skin Detachment, and Ulceration. She Responded Well to Discontinuation of TMP/sulfa, Early Short Course with Oral Prednisone, and Subsequent IVIG. Images Courtesy of Mary Wu Chang, MD.

Figure 3 A, B, C, D. An 18-Year-Old Female Developed SJS/TEN During Treatment with TMP/Sulfa. Widespread Painful, Purpuric Patches Developed on the Trunk and Extremities. Soon After, Bullae Developed from Necrosis and Skin Detachment, and Ulceration. She Responded Well to Discontinuation of TMP/sulfa, Early Short Course with Oral Prednisone, and Subsequent IVIG. Images Courtesy of Mary Wu Chang, MD.

Pain control is also vital but should be given cautiously. Although oral and cutaneous erosions can be very painful, care should be taken not to give enough opioid to lower the respiratory drive. Oral care is very important for pain control and to prevent infection. “Magic mouthwash” preparations containing various formulations of diphenhydramine and antacids with aluminum and magnesium help to debride the dead skin and also with pain control.

Monitoring for cutaneous, urinary tract, and pulmonary infections is vital. Prophylactic antibiotics are rarely indicated as they generally put patients at risk for resistant or atypical infections such as candidemia. Antibiotics should be guided by cultures and targeted to the most common pathogens that include Staphylococcus aureus, Enterobacteriae, Pseudomonas aeruginosa, and Candida species.20

Mortality in TEN may be able to be predicted by using a scoring method called SCORTEN at the onset of the disease. SCORTEN is likely more validated on adults as the criteria include age older than 40 years, renal status, percentage of body surface area involved, glucose, and heart rate and associated malignancy.21

Conclusion

Early recognition, prompt withdrawal of the offending agent, early therapeutics and meticulous wound care are key to therapy for SJS and TEN. Although this can be a life-threatening reaction, the mortality should decline with advances in therapeutics. Furthermore, future advances in pharmacogenomics may help to identify populations at risk for SJS or TEN from certain medications and lead to more individualized and judicious prescribing.

References

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Common Medication Causes of SJS/TEN

Sulfonamides Trimethroprim-sulfamethoxazole Sulfamethoxazole eye drops Sulfapyridine Sulfadoxine Silver sulfadiazine
Other antibiotics Penicillins Cephalosporins Minocycline Ciprofloxacin Terbinafine
Anticonvulsants Phenobarbital Carbamazepim Phenytoin Lamotragine
Other medications Allopurinol Nevirapine Non-steroidal Anti-inflammatory agents (NSAIDs) Sertraline
Authors

James Treat, MD, is Assistant Professor of Pediatrics and Dermatology, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia.

Dr. Treat has disclosed no relevant financial relationships.

Address correspondence to: James Treat, MD, is Assistant Professor of Pediatrics and Dermatology, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, 3550 Market Street, 2nd Floor Dermatology, Philadelphia, PA 19104; fax: 215-590-4948; e-mail: .treat@email.chop.edu

10.3928/00904481-20100922-11

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