eMedicine Specialties > Infectious Diseases > Skin and Soft-Tissue Infections

Toxic Epidermal Necrolysis

Author: Victor Cohen, PharmD, Clinical Pharmacy Manager, Department of Emergency Medicine, Maimonides Medical Center, Assistant Professor, Division of Pharmacy Practice, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University
Coauthor(s): Samantha P Jellinek, PharmD, BCPS, Clinical Coordinator of Pharmacy Practice Residency Program, Manager of Medication Reconciliation and Safety, Maimonides Medical Center; Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Feb 12, 2009

Introduction

Background

Toxic epidermal necrolysis (TEN) is a potentially life-threatening skin disorder that is most commonly drug induced. However, the disorder has other potential etiologies, including infection, malignancy, and vaccinations. Toxic epidermal necrolysis is idiosyncratic, and its occurrence is not easily predicted. Some authors believe Stevens-Johnson syndrome (SJS; also known as erythema multiforme) is a manifestation of the same process involved in toxic epidermal necrolysis, with the latter involving more extensive necrotic epidermal detachment. (Toxic epidermal necrolysis involves >30% of the body surface, whereas SJS involves <10%.)

Alan Lyell provided an early description of toxic epidermal necrolysis in 1956, describing the condition as "an eruption resembling scalding of the skin."1 This dermatological condition is characterized by extensive epidermal loss suggestive of severe scalding. In that same year, Lang and Walker also observed a patient with toxic epidermal necrolysis,2 which was originally described by Debre et al in 1939 in French as l'erythrodermie bulleuses avec epidermolyse.3 Lyell later reclassified the conditions of two of his patients as another disease, staphylococcal scalded skin syndrome,4 which is due to Staphylococcus aureus infection rather than to a probable drug hypersensitivity-type reaction. Histopathologic analysis of the skin remains the main tool for discrimination between the two conditions.

Pathophysiology

The pathophysiology of toxic epidermal necrolysis has not been fully elucidated; however, various theories have received wide acceptance. Toxic epidermal necrolysis is believed to be an immune-related cytotoxic reaction aimed at destroying keratinocytes that express a foreign antigen.

Toxic epidermal necrolysis mimics a hypersensitivity reaction, with its characteristic delayed reaction to an initial exposure and an increasingly rapid reaction with repeated exposure.

Explanations for the generalized nature of toxic epidermal necrolysis include the belief that tumor necrosis factor-α (TNF-α) is overexpressed in the epidermis. Therefore, TNF-α likely plays an important role in epidermal destruction directly through apoptosis, indirectly through stimulating cytotoxic T lymphocytes, or both.5

Frequency

United States

The frequency of toxic epidermal necrolysis is reported to be 0.22-1.23 cases per 100,000 population.

International

The average incidence of toxic epidermal necrolysis is 0.5-1.4 cases per million population per year. In 1992, the cumulative incidence of toxic epidermal necrolysis and SJS in Germany was 1.9 cases per million population. A French survey of dermatologists and health care facilities reported an incidence of 1 case per million population per year.

Mortality/Morbidity

Toxic epidermal necrolysis carries an estimated mortality rate of 10-70%, depending on the quality of care and the rapidity with which treatment is initiated. Morbidity depends on the aggressiveness of the treatment strategy. Toxic epidermal necrolysis heals slowly, with recovery taking 3-6 weeks, which depends on the extensiveness and severity of the lesions and associated complications.

  • Survivors of toxic epidermal necrolysis usually have long-term sequelae that are both debilitating and disfiguring.
  • Skin typically heals without scarring unless infection develops.
  • Disturbances in pigmentation are reported in 88% of cases.
  • The mortality risk in patients with toxic epidermal necrolysis can be accurately predicted using the toxic epidermal necrolysis–specific severity-of-illness score (SCORTEN).6 A score of 0-1 indicates a mortality risk of 3.2%; score of 2, 12.1%; score of 3, 35.3%; score of 4, 58.3%; and a score of 5 or more, 90%. Each of the following independent prognostic factors is given a score of one:
    • Age older than 40 years
    • Heart rate of greater than 120 beats per minute
    • Cancer/hematologic malignancy
    • Involved body surface area of greater than 10%
    • Serum urea level of more than 10 mmol/L
    • Serum bicarbonate level of less than 20 mmol/L
    • Serum glucose level of more than 14 mmol/L

Sex

For unclear reasons, toxic epidermal necrolysis appears to have more of a predilection for females than for males (female-to-male ratio of 1.6:1).

Age

  • Toxic epidermal necrolysis may occur in all age groups.
  • The mean age of patients with toxic epidermal necrolysis is reported to be between 46 and 63 years.
  • Elderly persons may be at greater risk because of their tendency to use multiple medications.

Clinical

History

  • Patients with toxic epidermal necrolysis (TEN) may describe a prodrome characterized by 2-3 days of malaise, rash, fever, cough, arthralgia, myalgia, rhinitis, headache, anorexia, and nausea and vomiting, with or without diarrhea.
  • Other prodromal signs and symptoms that may develop include conjunctivitis (32%), pharyngitis (25%), and pruritus (28%). The prodrome typically lasts from one day to as long as 3 weeks.
  • The acute phase of toxic epidermal necrolysis (8-12 d) is characterized by persistent fevers, generalized epidermal sloughing, and mucous membrane involvement. Complications include stomatitis and mucositis, which are painful and hinder oral intake; therefore, patients with these complications are at risk for dehydration and malnutrition.
  • The conjunctivae are commonly affected 1-3 days prior to the appearance of skin lesions.
  • Buccal, nasal, pharyngeal, and tracheobronchial denudation and erosion may occur.
  • Esophageal and perineal denudation and erosion may occur.
  • Vaginal, urethral, and anal mucosal denudation and erosion may occur.
  • The chief symptom is often generalized pain associated with a rash.

Physical

Vital signs in toxic epidermal necrolysis may include hyperpyrexia, hypotension secondary to hypovolemia, and tachycardia.

  • Skin examination
    • Skin lesions begin as painful/burning, warm, erythematous, morbilliform macules that are initially discrete. They begin symmetrically on the face and thorax before spreading to the entire body and becoming confluent. The epidermis sloughs in sheets, leaving a characteristic moist, denuded dermis. Denudation and erosions of mucous membranes precede epidermal necrolysis.
    • A positive Nikolsky sign is evident when pressure is applied laterally to the epidermal surface, and the epidermis easily separates from its underlying surface.
    • Hemorrhagic crusting of the lips is a common finding (as seen in the image below).

    • Hemorrhagic crusting of mucous membranes in toxic...

      Hemorrhagic crusting of mucous membranes in toxic epidermal necrolysis (TEN).

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      Hemorrhagic crusting of mucous membranes in toxic...

      Hemorrhagic crusting of mucous membranes in toxic epidermal necrolysis (TEN).

    • Conjunctivitis is commonly observed before full sloughing of the epidermis (with associated pain).
    • Pneumonia is a major complication of toxic epidermal necrolysis, resulting in acute respiratory failure and the need for intubation.
    • The usual course is an intense erythema that progresses rapidly to epidermolysis and stops within 2-3 days. Dermatologic recovery typically takes 1-3 weeks, with mucosal lesions taking longer. Rarely, necrolysis recurs in areas that began to heal.

Causes

Toxic epidermal necrolysis can be induced by drugs or infection or can be idiopathic. Frequent drug-induced causes include antiepileptic drugs, sulfonamides, ampicillin, allopurinol, and nonsteroidal anti-inflammatory drugs (NSAIDs).

  • Antibacterial sulfonamides - 4.5 cases per million users per week
    • Chloramphenicol
    • Macrolides (erythromycin)
    • Penicillins
    • Quinolones (ciprofloxacin,7 trovafloxacin8 )
  • Nonsteroidal anti-inflammatory drugs
    • Phenylbutazone and oxybutazone - Implicated most commonly, although they are no longer available in the United States
    • Oxicams (piroxicam, tenoxicam) - Implicated more often than other NSAIDs
    • Ibuprofen, indomethacin, sulindac, and tolmetin
  • Anticonvulsants
    • Phenobarbital, phenytoin,9 carbamazepine, and valproic acid: Toxic epidermal necrolysis has been reported within 2 months of initiation. However, some cases associated with long-term use have been reported.
    • Lamotrigine
  • Allopurinol
    • Risk is not constant over time.
    • Patients have a 5.5 relative risk. However, during the first 2 months of therapy, the relative risk is 52, and the long-term therapy risk is 0.5.
  • Topical and systemic corticosteroids

More on Toxic Epidermal Necrolysis

Overview: Toxic Epidermal Necrolysis
Differential Diagnoses & Workup: Toxic Epidermal Necrolysis
Treatment & Medication: Toxic Epidermal Necrolysis
Follow-up: Toxic Epidermal Necrolysis
Multimedia: Toxic Epidermal Necrolysis
References
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References

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Further Reading

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Keywords

toxic epidermal necrolysis, TEN, toxic epidermal necrosis, acute disseminated epidermal necrosis, acute skin failure, Lyell syndrome, Lyell’s syndrome, Stevens-Johnson syndrome, SJS-TEN

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Contributor Information and Disclosures

Author

Victor Cohen, PharmD, Clinical Pharmacy Manager, Department of Emergency Medicine, Maimonides Medical Center, Assistant Professor, Division of Pharmacy Practice, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University
Victor Cohen, PharmD is a member of the following medical societies: American Association of Colleges of Pharmacy, American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Samantha P Jellinek, PharmD, BCPS, Clinical Coordinator of Pharmacy Practice Residency Program, Manager of Medication Reconciliation and Safety, Maimonides Medical Center
Samantha P Jellinek, PharmD, BCPS is a member of the following medical societies: American College of Clinical Pharmacy and American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Fred A Lopez, MD, Associate Professor and Vice Chair, Department of Medicine, Assistant Dean for Student Affairs, Louisiana State University School of Medicine
Fred A Lopez, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, Infectious Diseases Society of America, and Louisiana State Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center
Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha Omega Alpha, American Association for the Advancement of Science, American Association of University Professors, American Clinical and Climatological Association, American College of Physician Executives, American College of Physicians, American Federation for Medical Research, American Foundation for AIDS Research, American Geriatrics Society, American Lung Association, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American Medical Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease Society for Obstetrics and Gynecology, Infectious Diseases Society of America, Louisiana State Medical Society, Orleans Parish Medical Society, Royal Society of Medicine, Sigma Xi, Society of General Internal Medicine, Southeastern Clinical Club, Southern Medical Association, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Association of Professors of Medicine, Association of Program Directors in Internal Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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