Stevens-Johnson syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare cutaneous diseases marked by substantial epidermal denudation and are often complicated by sepsis and multiple organ failure. They are most commonly caused by drug therapy. Patients afflicted with these diseases require care that may exhaust the capabilities of medicine wards and medical intensive care units alike; however, their mortality is reduced when treated at bum centers, which are better equipped to treat extensive skin denudation. We report a case of TEN and propose an algorithm to provide guidance for making the critical decision to transfer patients with SJS and TEN to burn units.

Introduction

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are grave disorders with mortality rates ranging from 20 to 30%. 1-4 The incidence of SJS is 1 to 6 cases per million person-years, and the incidence of TEN is 0.4 to 1.2 cases per million person-years.2,5-7 The classification of these disorders is confusing. SJS is an acute mucocutaneous disease defined as a rapidly expanding macular eruption affecting less than 10% of body surface area (BSA) and involving more than one mucosal surface (oral, conjunctival, or anogenital). The overlapping entity of SJS-TEN is described as a disorder with 10 to 30% epidermal involvement. A diagnosis of TEN requires involvement of greater than 30% of BSA.3,4,8

Clinically, SJS and TEN are heralded by an influenza-like prodrome.8,9 A tender erythematous macular eruption appears on the face, neck, trunk, and extremities. There is a rapid evolution in the number and size of skin lesions, some of which may have a targetoid appearance with dusky centers. With time, the lesions become confluent, often forming flaccid bullae and hemorrhagic blisters. Nikolsky's sign may be present, and the loss of sheets of necrotic epidermis often results in large erosions. Most often, maximal body surface involvement is reached within 1 to 5 days.8

The proposed cause of SJS and TEN is a cytotoxic cellular immune reaction against keratinocytes that express culprit drug-induced antigens.8 Cytokine-mediated apoptosis of keratinocytes is responsible for cell destruction.10 Both CD4 and CD8 T cells are involved, with little evidence of humoral involvement.8,11 The dermis remains largely unchanged.11

Case Report

A 46-year-old African-American woman with a past medical history of alcoholic cirrhosis and diabetes mellitus presented with complaints of fatigue for 1 week, productive cough, polyuria, and a painful erythematous eruption on the palms and soles. One month before admission, she started a new drug regimen, which included furosemide, spironolactone, prednisolone, omeprazole, and lactulose. Initial physical examination was remarkable for stigmata of chronic liver disease, a palatine ulcer, and diffuse erythematous macules on the chest, back, and sacrum. Tender erythematous macules and patches occasionally containing petechiae were also present on the palms and soles (Fig. 1).

Initial laboratory values were consistent with cirrhosis and hyperglycemia. A skin biopsy of the right sole was consistent with erythema multiforme. All medications were stopped, and the patient was eventually weaned off of corticosteroids. Within days after admission, the patient developed oral and anogenital erosions, and by hospital day 10, she had approximately 10% epidermal denudation.

At this time, an unsuccessful attempt to refer the patient to a bum center was made. By hospital day 18, the patient had progressed to TEN, with involvement of 50 to 60% of BSA. The patient required wound care and intensive medical management that were beyond the capabilities of the medical intensive care unit. On the 19th hospital day, the patient was transferred to a burn center. The hospital course was complicated by renal failure, hepatic encephalopathy, sepsis, and respiratory failure. On the 40th day after admission, care was withdrawn and the patient died.

Discussion

The decision to transfer a patient with SJS or TEN to a bum center is often the most important therapeutic intervention. Halebian et al.12 first demonstrated that treating patients with SJS and TEN at a bum center without corticosteroids decreased mortality. Subsequently, Heimbach13 and colleagues established that early referral to a bum center significantly decreased the mortality of patients with SJS and TEN. In spite of these findings, McGee and Munster14 noted that corticosteroids continue to be used and that delay exists in transferring patients to bum centers.

The approach to a patient suspected of having SJS or TEN includes a thorough history and physical examination and a skin biopsy.11,15-19 A differential diagnosis of blistering disorders causing denudation is listed in Table I.8,9,20 Biopsy results are helpful in differentiating these disease processes.

Drugs are the precipitating agents in approximately 90% of SJS and TEN cases; therefore, all nonessential medications should be stopped.5,6,8 Additionally, Garcia-Doval2l and colleagues showed that the prognosis is significantly improved the more rapidly the offending medication is discontinued. Medications with established increased risk include antibacterial sulfonamides, anticonvulsant agents, oxicam nonsteroidal antiinflammatory drugs, allopurinol, chlormezanone, and corticosteroids. The increased risk for SJS and TEN with these drugs is usually limited to the first 2 months of use.5

In our case, the most likely offending medications were corticosteroids and furosemide. Although both medications have been implicated in SJS and TEN, only corticosteroids have an increased relative risk with their use.5,9 A 1995 case-control study demonstrated that when adjusted for other variables, patients taking corticosteroids are 12 times more likely to develop SJS or TEN than those not taking corticosteroids.5 Only one case report exists of TEN attributed to omeprazole.22 A search of the English-language literature failed to reveal case reports of JS or TEN attributable to spironolactone and lactulose, the other medications our patient was taking on admission.

The threshold for rapid referral should be governed by three established prognostic factors for SJS and TEN: the percentage of BSA involved, patient age, and the presence of significant comorbid illness. Increased percentage of BSA involvement has been shown to portend a poor outcome.1,12,16,17,23 In a retrospective study involving 87 patients with SJS and TEN over 13 years, Revuz et al.1 revealed that the average patient who survived had a BSA involvement of 35% or less. Several more recent but smaller studies of SJS and TEN patients who were treated at bum centers demonstrated that the average percentage of BSA involved in surviving patients ranged from 41 to 56%.12,16,23 Based on these data, we conservatively recommend that patients with an estimated 35% of BSA involved be transferred to a burn center.

Halebian and others have consistently shown that increased age is also a poor prognostic indicator for SJS and TEN.1,2,11,12,16 In a large retrospective study of 253 patients from 1981 to 1985, the average age of surviving patients was 41 years, whereas the average age of nonsurviving patients was 61 years.2 In smaller retrospective studies, the average age of survivors ranged from 30 to 40 years, whereas the average age of nonsurviving patients was 54 to 61 years.1,12,16 Based on these studies, we recommend that patients older than 40 years suspected of having SJS or TEN should be considered for transfer to a bum center with greater haste.

Halebian et al.12 also demonstrated that comorbid illnesses (diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, seizure disorder, and human immunodeficiency virus infection) are associated with an increased risk of mortality. Consequently, the threshold for transfer to a burn unit should be decreased appropriately for patients with these illnesses.

The necessity for early transfer to a bum unit should not be underestimated. Transfer within 7 days has been associated with a favorable outcome. In 1987, Heimbach13 and colleagues showed a reduction in mortality to less than 20% among 19 patients who were transferred to a bum unit within 7 days of presentation. In a review of 36 patients, McGee and Munster14 demonstrated that those who were referred within 7 days had a 4% mortality, whereas those transferred after 7 days had a mortality of 83%. Furthermore, patients who survived were transferred an average of 7.5 days sooner than nonsurviving patients.14 Kelemen et al. reviewed 37 patients and found that after controlling for other variables, patients who were transferred to a bum center after 7 days of epidermal sloughing had an average hospital stay of twice as long as those transferred before 7 days. 16

Recognizing the significance of referral within 7 days, we have proposed an algorithm based on the percentage of BSA involved, patient age, and the presence of comorbid illness to help physicians decide when to transfer patients with SJS or TEN to a burn center (Fig. 2).

Burn centers are best prepared to care for SJS and TEN patients because they have multidisciplinary care teams with specific wound care protocols and equipment and are experienced at managing critically ill patients. The mortality associated with SJS and TEN arises from wound infection leading to sepsis and multiorgan failure.1,11-14,23 Grave complications involving nearly every organ system frequently compound the severity of SJS and TEN. For example, up to 70% of patients require intubation for respiratory failure during their hospital course." For these reasons, wound care to prevent infection is the crux of patient care.24,25

Barillo and Goodwin15 pointed out that burn units are "wound intensive care units" and that denuding diseases, including SJS and TEN, are the second most common disorder treated in burn centers. The extensive denudation seen in SJS and TEN is not entirely similar to that seen in thermal injuries, because it does not principally cause dermal injury.25 Unlike thermal injuries, &JS and TEN wounds do not cause patients to have exponentially increased metabolic and fluid requirements, and overall healing is more rapid.13,18,26,27 Additionally, re-epithelialization begins within days of denudation."

In Yarbrough's series of 16 patients with TEN treated at a burn center, who had an average of 80% BSA involvement, re-epithelialization was complete within 16 days for the 12 surviving patients.17 Extensive wound care, whether thermal or not, may require 25 man-hours per patient in a bum unit, which can easily overwhelm a hospital's capabilities.15 Patients with SJS and TEN usually have extensive mucosal involvement and need one-on-one special nursing care by staff members who are familiar with the management of such lesions.12,15,17,25,28

Conclusion

SJS and TEN are rare diseases with a higher mortality rate when treated outside of a bum unit. We have proposed a literature-based algorithm to guide the referral of SJS and TEN patients to a bum center. Patients who meet the criteria based on the percentage of BSA involved, age, and the presence of comorbid illness should be transferred to a bum center within 7 days of diagnosis.

References

1. Revuz J, Penso D, Roujeau J-C, et al: Toxic epidermal necrolysis: clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987; 123: 1160-5.

2. Roujeau J-C, Guillaume J-C, Fabre JP, Penso D, Flechet M-L, Girre J-P: Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990; 126: 37-42.

3. Kelly JP, Auquier A, Rzany B, et al: An international collaborative case-control study of severe cutaneous adverse reactions (SCAR): design and methods. J Clin Epidemiol 1995; 48: 1099-1108.

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7. Chan H-L, Stem RS, Arndt KA, et al: The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Arch Dermatol 1990; 126: 43-7.

8. Fritsch PO, Ruiz-Maldonado R Stevens-Johnson syndrome-toxic epidermal necrolysis. In Fitzpatrick's Dermatology in General Medicine. Edited by Freedberg IM. New York, McGraw-Hill, 1999.

9. Araujo OE, Flowers FP: Stevens-Johnson syndrome. J Emerg Med 1984; 2: 129-35.

10. Paul C, Wolkenstein P, Adle H, et al: Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 1996; 134: 710-4.

11. Roujeau J-C, Chosidow 0, Saiag P, Guillaume J-C: Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990; 23: 1039-58.

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16. Kelemen JJ III, Cioffi WG, McManus WF, Mason AD Jr, Pruitt BA Jr: Bum center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995; 180: 273-8.

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19. Rasmussen JE: Erythema multiforme: should anyone care about the standards of care? Arch Dermatol 1995; 131: 726-9.

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21. Garcia-Doval 1, LeCleach L, Bocquet H, Otero X-L, Roujeau J-C: Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000; 136: 323-7.

22. Cox NH: Acute disseminated epidermal necrosis due to omeprazole. Lancet 1992; 340: 857.

23. Ward DJ, Krzeminska EC, Tanner NS: Treatment of toxic epidermal necrolysis and a review of six cases. Bums 1990; 16: 97-104.

24. Marvin JA, Heimbach DM. Engrav LH, Hamar TJ: Improved treatment of the Stevens-Johnson syndrome. Arch Surg 1984; 119: 601-5.

25. Halebian PH, Shires GT: Burn unit treatment of acute, severe exfoliating disorders. Annu Rev Med 1989; 40: 137-47.

26. Pruitt B: Bum treatment for the unburned. JAMA 1987; 257: 2207-8.

27. Zoltie N, Verlende P, O'Neill TJ, McKenzie AW: Lyell's syndrome on a burns unit. Burns 1994; 20: 368-70.

28. Englehardt SL, Schurr MJ, Helgerson RB: Toxic epidermal necrolysis: an analysis of referral patterns and steroid usage. J Bum Care Rehabil 1997; 18: 520-4.

Guarantor: CPIF Michael W. Ellis, MC USA

Contributors: CPT Michael W. Ellis, MC USA; COL Charles N. Oster, MC USA; LTC George W. Turiansky, MC USA; MAJ Jeremy R Blanchard, MC USA

Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307-5001.

Presented in part at the American College of Physicians-American Society of Internal Medicine Associates Meeting (Washington, DC, chapter), May 13, 2000.

This manuscript was received for review in July 2001. The revised manuscript was accepted for publication in February 2002.

Copyright Association of Military Surgeons of the United States Aug 2002
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