Toxic Epidermal Necrolysis: Report of a Fatal Case of Recurrent Disease and Literature Review

Toxic epidermal necrolysis (TEN) is a rare, acute, life-threatening condition characterized by severe epithelial detachment of the skin and mucous membranes and usually is seen as part of an idiosyncratic drug reaction.¹ Mortality rates of 15–40% have been reported, usually due to multi-organ failure and infection.^2–4 Until recently, supportive care was the mainstay of therapy. The authors report a fatal case of TEN and discuss the management of afflicted patients. Case Report A 69-year-old black man with acquired immunodeficiency syndrome (AIDS), end-stage renal disease requiring hemodialysis, chronic hepatitis C infection, diabetes mellitus, and hypertension was admitted for evaluation of a new blistering rash. His recent history included 2 hospital admissions within the 4 months prior to admission for Clostridium difficile colitis and methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. During these hospitalizations, the patient was treated with multiple courses of oral metronidazole and vancomycin for C. difficile colitis and discharged to a skilled nursing facility to complete a 14-day course of intravenous vancomycin administered at hemodialysis for MRSA bacteremia. One day prior to admission, the patient presented for routine hemodialysis and administration of vancomycin through his dialysis catheter. During hemodialysis, a nurse noted hemorrhagic crusting of the patient’s lips as well as erythema of the hands. On the day of admission, the patient again presented for hemodialysis, was found to have progression of his rash, and was referred for admission. He complained of soreness in his mouth, which made eating difficult for the 2 days prior to admission. On the day of admission, he also reported that his hands were sore. He denied fever, chills, dysuria, eye pain, or pain involving the remainder of his skin. On presentation, the patient was in no acute distress with a temperature of 98.5°F, a pulse of 90 beats/minute, and blood pressure of 102/65 mmHg. His conjunctivae were mildly erythematous, and both upper eyelids had superficial erosions. His oral cavity revealed multiple shallow, 2–3 mm erosions with hemorrhagic crusting extending from the lips to the soft palate. His right chest revealed a 2 cm x 3 cm full-thickness erosion. Both palms had full-thickness, necrotic erosions with surrounding, partially blanching erythema of the digits. The soles of both feet were erythematous without erosions. The left lower leg had a small circular erosion. Cardiopulmonary, abdominal, extremity, and neurological examinations were unremarkable. On presentation, the patient’s medications were vancomycin administered at hemodialysis, trimethoprim-sulfamethoxazole, gabapentin, amlodipine, sertraline, and metoprolol. He had a known allergy to piperacillin-tazobactam. He had a prior history of cigarette and ethanol abuse but had not used either substance in the months prior to presentation. His past medical history included AIDS with a CD4 count of 106 cells/mm³ and a viral load of 700 copies/mL. Leading up to presentation with the blistering rash, the patient was hospitalized for 4 months and did not receive any highly active antiretroviral therapy (HAART). He was maintained on hemodialysis for end-stage renal failure secondary to diabetic glomerulosclerosis, and 6 days prior, during his hospitalization for MRSA bacteremia, his dialysis catheter was changed. In the hours following admission, the patient was observed to have continued progression of his rash with new erosions appearing on the right hip and buttocks with extension of the erosions in the oral cavity (Figures 1–4). Given the rapid progression of the oral erosions and full-thickness necrotic lesions on the palms, the patient was presumptively diagnosed with evolving Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and transferred to the intensive care unit. Soon after presentation, dermatology consultants saw the patient, and 2 punch biopsies of the right hand were performed. A Tzanck preparation of a skin lesion did not reveal multinucleated giant cells. Laboratory examination revealed a white blood cell count of 11.7/mm³, hematocrit of 30.8%, and a platelet count of 287/mm³. Electrolytes were significant for a serum bicarbonate of 32 mmol/L, phosphorus of 1.0 mg/dL, and potassium of 4 mmol/dL. Liver function tests were within normal limits—blood urea nitrogen (BUN) was 6 mg/dL, and glucose was 108 mg/dL. Serum protein and albumin were 6.5 g/dL and 2.8 g/dL, respectively. A chest radiograph revealed a dialysis catheter that appeared to be normal but did not reveal any pulmonary pathology. Soon after admission, the patient was started on intravenous immunoglobulin (IVIg) therapy at a dose of 1 gm/kg/day for 4 days for the presumptive diagnosis of SJS/TEN. All possible offending medications were held, including vancomycin, trimethoprim-sulfamethoxazole, metoprolol, amlodipine, gabapentin, and sertraline. The patient was treated with linezolid for continued management of MRSA bacteremia. During the 4 days of IVIg therapy, the patient’s skin examination markedly improved, and no new skin lesions were observed. On Day 2 of hospitalization, the patient’s skin biopsy revealed full-thickness necrosis of the epidermis, confirming the diagnosis of TEN. He was able to tolerate a normal diet and on Day 8 of hospitalization was discharged to a skilled nursing facility. His medications at the time of discharge were linezolid, gabapentin, pancrealipase, and regular insulin. He also received inhaled pentamidine prior to discharge to be administered monthly for Pneumocystis carnii prophylaxis. Four weeks after discharge with TEN, the patient was readmitted with recurrent fevers and lethargy. Given his family’s refusal to consent to a lumbar puncture, he was presumptively treated for meningitis/encephalitis with linezolid, ceftriaxone, and acyclovir. Ultimately, the patient was found to have osteomyelitis of the right foot and was treated with linezolid and gatifloxacin with resolution of the fever and improvement in mental status. Despite antibiotic therapy, the patient continued to have fevers with a nonhealing lower-extremity wound and was scheduled for a right above-the-knee amputation. On Day 48 of hospitalization, the patient was started on intravenous ceftriaxone and linezolid for a new fever of unknown etiology. On Day 53 of hospitalization, the patient developed a rash following 2 days of skin discomfort. Of note, physical examination revealed that the patient was afebrile, normotensive, had a pulse of 74 beats/minute, and had diffuse erythroderma with cheek desquamation and flaccid bullae on the right wrist and right thigh. Both palms were diffusely erythematous with evidence of desquamation. Blood chemistries were significant for a BUN of 47 mg/dL, glucose of 76 mg/dL, and serum bicarbonate of 19 mmol/L. At the time of this rash, his medications included ceftriaxone, metronidazole, linezolid, gabapentin, metoprolol, and regular insulin. A frozen section of a biopsy taken from the roof of a flaccid bulla on the right wrist revealed full-thickness epidermal necrosis with necrotic keratinocytes. A diagnosis of TEN was made based on the clinical examination and the frozen section pathology. The patient was transferred to the intensive care unit for management of presumed recurrent TEN. A punch biopsy of the hand revealed full-thickness epidermal necrosis, consistent with TEN. All possible offending medications were again discontinued, and he was administered IVIg at a dose of 2 gm/kg/day. Despite receiving aggressive fluid support and wound care, the patient’s skin lesions did not heal after 5 days of IVIg. On Day 62 of hospitalization, the patient’s family opted to provide comfort measures, and the patient expired. Clinical Presentation A discussion of TEN should also include the closely related conditions of erythema multiforme and SJS. These conditions are characterized by lesions of the skin and mucous membranes that are induced by drug exposure or infection. While there are many presentations of erythema multiforme, the classic lesional form is a highly regular circular, wheal-like plaque or papule with a central violaceous or dusky core. In 1922, Stevens and Johnson⁵ described children with disseminated eruptions of discrete red macules, ocular involvement, stomatitis, and fever. Compared with erythema multiforme, patients with what is now known as SJS have more widely distributed macules and blisters, commonly on the trunk and face, and more severe mucosal involvement, often at 2 or more mucosal sites. In 1956, Lyell⁶ described TEN with rapid, widespread epidermal necrolysis resembling scalding. A large, international, prospective study found that erythema multiforme differs from SJS and TEN not only in severity but also in suspected causes and demographic characteristics.⁷ Stevens-Johnson syndrome is most commonly associated with an offending medication, whereas erythema multiforme is most likely associated with infection, such as with herpes simplex infection, which accounts for 60% of cases.⁸ While debate exists whether all 3 entities are identical processes that differ only in the extent and severity of body surface involvement, many authors agree that SJS and TEN are closely related.¹ While there can be epidermal detachment in SJS (usually less than 10% of body surface area), patients with TEN have a more profound loss of epidermis (greater than 30% of body surface area) that can leave the skin surface with a scalded appearance. When 10–30% of body surface area is involved, it is often referred to as SJS/TEN overlap. Epidemiology Though less common than SJS, TEN has an incidence between 0.4 and 1.2 cases per million per year,⁹ and in adults, there is a slight increased risk in females.¹⁰ More than 100 different medications have been associated with TEN development. A study of patients with SJS or TEN found the medications most commonly associated with these conditions were sulfonamide and non-sulfonamide antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, allopurinol, chlormezanone, and corticosteroids. Of these medications, sulfonamides have the highest association.⁹ Pathogenesis Pathologically, TEN is characterized by widespread keratinocyte cell death resulting in sloughing of the epidermis at the dermal-epidermal junction. Inflammatory infiltrate in affected areas is typically sparse, containing predominately CD8+ cytotoxic T-lymphocytes (CTLs).^11,12 In early lesions, keratinocyte death occurs through apoptosis,¹³ a regulated form of cell suicide and disassembly characterized by DNA fragmentation, nuclear condensation, and membrane blebbing. In advanced lesions, full-thickness necrosis (or necrolysis) is apparent as the epidermis detaches from underlying dermis and viability is lost. Although the pathogenesis of TEN is incompletely understood, it has long been suspected to result from an acquired immunologic response against the offending drug (or its metabolites), which may form haptens on epithelial cell membranes.¹⁴ The typical delay in onset of symptoms following initial drug administration is often 1 to 3 weeks, but rapid recurrence of symptoms after re-challenge (typically 48 hours or less) is consistent with an acquired immune response.¹⁵ Furthermore, CTLs isolated from blister fluid of TEN patients have been shown to specifically kill autologous B-lymphocytes or keratinocytes in vitro when the initiating drug is present.¹⁶ Genetic predisposition to TEN has been associated with HLA-B12¹⁷ and with an impaired ability to eliminate particular drugs or their metabolites.^18,19 Despite evidence implicating drug-specific CTLs in pathogenesis of TEN/SJS, the relative paucity of infiltrating cells suggests that additional mechanisms contribute to pathogenesis. Cytotoxic T-lymphocytes express the death-inducing protein Fas ligand (FasL), which induces apoptosis by engaging Fas (CD-95) on target cells, including keratinocytes. Viard et al.²⁰ demonstrated that in skin of TEN patients, keratinocytes begin to express high levels of FasL, which may engage Fas expressed on the same or adjacent cells, leading to widespread cell suicide/fratricide. Intriguingly, Viard et al.²⁰ also demonstrated that pre-incubation of cultured keratinocytes with IVIg protected against killing by soluble FasL, suggesting an explanation for the clinical usefulness of IVIg in treating TEN. The precise signals leading to keratinocyte upregulation of FasL expression are unknown. The cells may respond to a feedback loop initiated by the initial CTL-mediated injury and subsequent elaboration of inflammatory cytokines.²¹ Blister fluid near sloughing epidermis is typically rich in tumor necrosis factor (TNF), soluble FasL, IL-6, and IL-2, all of which may play a critical role in accelerating tissue damage.¹⁴ Severity of Illness SCORTEN, an illness severity scale specific to TEN, has been used to predict mortality of patients with TEN on admission.²² The scale uses 7 independent prognostic factors: age > 40 years, heart rate > 120 beats/min, presence of cancer or hemopathy, detached body surface area > 10%, BUN level > 27 mg/dL, serum bicarbonate concentration 252 mg/dL. Absence of risk factors or presence of 1 risk factor is associated with a 3% mortality, which increases to 21.1% mortality with 2 risk factors, 35% with 3 risk factors, 58% with 4 risk factors, and 90% with 5 or more risk factors. Treatment Once the diagnosis is made, prompt attempts at identification and withdrawal of the offending agent should be made and may lead to decreased mortality. However, the elimination half-life of the medication may have some prognostic importance. For example, a study found that early withdrawal of offending medications with short half-lives decreased mortality rate from 26% to 5%, while early withdrawal of medications with half-lives longer than 24 hours did not improve survival.²³ In addition to withdrawing the suspected agent responsible, chemically-related medications should be avoided.²⁴ Whenever possible, patients should be treated in burn units and receive care usually provided to burn victims: protection of eroded surfaces, infection control, nutritional support, careful monitoring, and control of fluids and electrolytes.²⁵ While some patients can be managed conservatively wherein excessive debridement is avoided and detached epidermis is secured “on site” using dressings and topical antiseptics,²⁶ some patients may require debridement of necrotic tissue and covering of erosions with heterografts, homografts, and synthetic allografts.²⁷ The pathogenesis of TEN may be due to abnormal T cell recognition of a keratinocyte-drug complex that leads to the production of large amounts of active FasL by keratinocytes to interact with keratinocyte surface Fas receptors that culminate in cell death. Efforts at interrupting this pathway have been undertaken. The finding that pooled human immunoglobulin (Ig) can block Fas-mediated keratinocyte apoptosis in vitro has led to several reports evaluating the efficacy of IVIg in the treatment of TEN. Intravenous immunoglobulin has been shown to be effective in adults^28–32 and children with SJS and TEN.³³ However, data from prospective, blinded, randomized, controlled trials demonstrating improvement in the mortality rate of TEN with IVIg are lacking. While some retrospective studies suggest there may be a decrease in mortality,^28,29 other studies have tempered some of the initial enthusiasm for IVIg^34–36 and have underscored the need for additional trials. Glucocorticoids, cyclosporin A, N-acetylcysteine, pentoxifylline, cyclophosphamide, thalidomide, and anti-TNF-alpha antibodies have all been proposed as therapy for TEN,²⁵ though none have conclusively been shown to be beneficial. Therapy with these agents is not recommended at this time. Conclusion The authors’ patient with AIDS, renal failure, and recurrent TEN ultimately succumbed to the disease, despite the administration of IVIg. While IVIg has been reported to have been successfully employed in patients with advanced HIV,³⁷ it is possible that this patient’s unfortunate outcome might be attributed to the fact that he was experiencing a second bout of TEN. Since TEN is presumed to be a specific immune response, a recurrent exposure to the trigger should induce a more brisk and intense (and in this case fatal) episode. Alternatively, his considerable comorbidities might have contributed to his ultimate demise in the face of TEN. In any event, healthcare providers should be vigilant about diagnosing this disease that carries considerable morbidity and mortality, as early intervention has the potential to lessen suffering caused by this entity.