Toxic Epidermal Necrolysis (TEN) 

Updated: Jul 01, 2021
Author: Samantha P Jellinek-Cohen, PharmD, BCPS (AQ-ID); Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatologic disorder characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes, resulting in exfoliation and possible sepsis and/or death. Mucous membrane involvement can result in gastrointestinal hemorrhage, respiratory failure, ocular abnormalities, and genitourinary complications.

Diffuse maculopapular rash in toxic epidermal necr Diffuse maculopapular rash in toxic epidermal necrolysis (TEN).

TEN is most commonly drug induced. However, the disorder has other potential etiologies, including infection, malignancy, and vaccinations. TEN is idiosyncratic, and its occurrence is not easily predicted.

Some authors believe that Stevens-Johnson syndrome (SJS; also known as erythema multiforme major) is a manifestation of the same process involved in TEN, with the latter involving more extensive necrotic epidermal detachment. TEN involves more than 30% of the body surface, whereas SJS involves less than 10%.

A classification system, based largely on the extent of epidermal detachment and morphology of the skin lesions, aids in differentiating opposite spectrums of the same disease entity.[1] This system comprises the following:

  • TEN with spots
  • TEN without spots
  • Overlap Stevens-Johnson syndrome and TEN (SJS-TEN)

TEN with spots is defined as widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Blisters become more confluent and result in detachment of the epidermis and erosions on greater than 30% of the body surface area. Mucosal surfaces are usually involved.

TEN without spots is defined as widespread, large areas of erythema with no discrete lesions. Epidermal detachment is greater than 10% of the body surface area. Mucosal surfaces are usually involved.

Overlap Stevens-Johnson syndrome and TEN (SJS-TEN) is characterized by widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Blisters become confluent and result in detachment of the epidermis and erosions on 10-29% of the body surface area.

TEN is a clinical diagnosis, confirmed by histopathologic analysis of lesional skin. The mainstay of treatment is supportive care until the epithelium regenerates. Early transfer of patients to a burn or intensive care unit has been shown to reduce the risk of infection, mortality rate, and length of hospitalization.

Historical background

Alan Lyell provided an early description of TEN in 1956, describing the condition as "an eruption resembling scalding of the skin."[2] This dermatologic condition is characterized by extensive epidermal loss suggestive of severe scalding. In that same year, Lang and Walker reported a case of TEN.[3] The disorder was originally described by Debre et al in 1939 in French as l'erythrodermie bulleuses avec epidermolyse.[4]

Lyell later reclassified the conditions of 2 of his patients as having staphylococcal scalded skin syndrome,[5] 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.

Patient education

Patients who have had TEN must be counseled regarding the likely causative medication or agent, and they must be advised to avoid these medications and those of the same or similar classes in the future. Cross-reactivity may occur with agents that chemically resemble the causative agent. Patients must call a pharmacist whenever they start a new prescription.

The patient should be educated on any medical treatment that is still necessary and on sun protection to prevent post-inflammatory hyperpigmentation. There are several long-term complications in patients surviving TEN and the patient should be educated on the prognosis and the need for follow-up. At discharge, patients should be asked to complete the General Health Questionnaire-12 and scores of 2 or greater should trigger a referral to a psychiatrist or psychologist. Information on available support groups should be given to the patient.[6]

Genetic factors are suspected in drug-induced blistering disorders, and blood relatives of the patient also should not use the suspected drug.

For patient education information, see the Skin, Hair, and Nails Center, as well as Life-Threatening Skin Rashes.

Pathophysiology

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

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

The widespread epidermolysis and blistering of TEN results from keratinocyte apoptosis—an organized series of biochemical reactions leading to cell changes and cell death.[7] However, the number of inflammatory T cells in the skin of patients with TEN is variable and perhaps too low to explain the widespread destruction.[8]

There is evidence supporting several immunopathologic pathways leading to keratinocyte apoptosis in TEN, including the following:

  • Fas ligand activation on keratinocyte membranes leading to death receptor–mediated apoptosis[9]

  • Release of destructive proteins (perforin and granzyme B) from cytotoxic T lymphocytes (CTLs) generated from an interaction with cells expressing major histocompatability complex (MHC) class I[10]

  • Overproduction of T cell– and/or macrophage-derived cytokines (interferon-γ [INF-γ], tumor necrosis factor-α [TNF-α], and various interleukins)[11, 12]

  • Drug-induced secretion of granulysin from CTLs, natural killer cells, and natural killer T cells[13]

Precisely how the inciting agent triggers the proposed pathways is yet to be elucidated.

Etiology

TEN can be induced by drugs or infection or can be idiopathic. Medications are the major precipitating cause. Numerous medications have been implicated,[14] including antibiotics, antiepileptic drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), ampicillin, allopurinol, corticosteroids (topical and systemic), and the antiretroviral drugs nevirapine and abacavir.[15, 16]  TEN usually occurs during the first course of therapy with a drug (ie, without sensitization).

Antibacterial drugs associated with TEN include the following:

  • Sulfonamides (4.5 cases per million users per week)
  • Chloramphenicol
  • Macrolides (eg, azithromycin, clarithromycin, erythromycin, telithromycin) [17]
  • Penicillins
  • Quinolones (eg, ciprofloxacin, [18] trovafloxacin [19] )

Anticonvulsants associated with TEN include the following:

  • Phenobarbital
  • Phenytoin [20]
  • Carbamazepine
  • Valproic acid
  • Lamotrigine

TEN in patients taking anticonvulsants has most often been reported within 2 months of starting the drug. However, some cases associated with long-term use have been reported.

NSAIDs associated with TEN include the following:

  • Phenylbutazone and oxybutazone - Implicated most commonly, although they are no longer available in the United States
  • Oxicams (eg, piroxicam, tenoxicam) - Implicated more often than other NSAIDs
  • Ibuprofen
  • Indomethacin
  • Sulindac
  • Tolmetin

With 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.

No laboratory test is able to confirm a specific drug etiology. A causal link is suggested when TEN occurs during the first 4 weeks of medication therapy, usually between 1 and 3 weeks. Drugs with longer half-lives and those with circulating active metabolites may result in more fulminant disease.

Infectious agents (ie, Mycoplasma pneumoniae, herpes virus, hepatitis A), immunizations (eg, meningococcal vaccine), and bone marrow or solid organ transplantation have also been associated with TEN.[21]

Epidemiology

In the United States, the annual frequency of TEN is reported to be 0.22-1.23 cases per 100,000 population. In the HIV-positive population, the incidence of TEN increases to 1 case per thousand per year.[22]

Worldwide, the average annual incidence of TEN is 0.4-1.3 cases per million population.[23] In 1992, the cumulative incidence of TEN and SJS in Germany was 1.9 cases per million population. A French survey of dermatologists and health care facilities reported an annual incidence of 1 case per million population.

Race-, sex-, and age-related demographics

A genetic predilection toward carbamazepine-induced TEN has been observed in HLA-B*1502–positive patients in mainland southeast Asian people from China to India. The US Food and Drug Administration recommends screening for the HLA-B*1502 allele before initiating carbamazepine in patients of Asian ancestry.[24]  The HLA-B*58:01 allele is associated with allopurinol-induced TEN in Han Chinese people. HLA-A*66:01, HLA-B*44:03, and HLA-C*12:03 have been associated with cold medicine-TEN with severe ocular complications in patients who had taken cold medicines in the 1-14 days prior to onset of the disease. The HLA-B*44:03 (odds ratio, 5.50) and HLA-C*12:03 (OR, 8.79) alleles were associated with a less-robust tisk of cold medicine-TEN only in European patients.[25]

Registration databases from Tawain, Thailand, Japan, Malaysia, Singapore, Hong Kong, the Philippines, and mainland China (Fujian) identified that from 1998-2017, greater than 50% of cases of SJS/TENS involved carbamazepine, allopurinol, phenytoin, lamotrigine, and sulfamethoxazole.  Oxacarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate (not approved by the Food and Drug Administration but used in more than 70 countries as a treatment option for postmenopausal osteoporosis) have been identified as potential new causes of SJS/TENS in Asian patients.  Other medications known to cause SJS/TENS such as oseltamavir, terbinafine, and sorafenib, were not associated with any cases in Asian patients enrolled in these databases.[26]

For unclear reasons, TEN appears to have a predilection for females. The female-to-male ratio is 1.5:1.[27]

TEN may occur in all age groups; however, the mean age of patients with TEN is reported to be between 46 and 63 years. Infection is more commonly implicated as an etiology in children, whereas medication exposure is more common in adults. Elderly persons may be at greater risk because of their tendency to use multiple medications.

Prognosis

The estimated mortality associated with TEN varies widely in different reports, from 10-70%. Outcome depends in part on the quality of care and the rapidity with which treatment is initiated.

The re-epitheliazation period lasts between 1 and 3 weeks, depending on the extent and severity of the clinical picture.[28]

Septicemia and multisystem organ failure are the primary causes of death. Epithelial loss results in vulnerability to bacterial and fungal infections. Sloughing of stratified epithelium of mucosal membranes can result in GI hemorrhage, respiratory failure, ocular abnormalities, and genitourinary lesions. Significant fluid loss from extensive skin exfoliation and an inability to tolerate oral intake can lead to hypovolemia, acute tubular necrosis, and shock.

Age, extent of epidermal involvement, and serum urea level are said to be the most important prognostic factors in TEN.[29] Mortality rates in children are much lower than in adults.[30] Elderly patients have a poor prognosis.

Other negative prognostic factors include the following:

  • Elevated blood urea nitrogen (BUN) and serum creatinine levels

  • Respiratory failure

  • Multiple drugs

  • Thrombocytopenia

  • Lymphopenia

  • Neutropenia

  • Leukopenia

  • Sepsis

Severity-of-illness score

A severity-of-illness score that estimates the risk of death in TEN (SCORTEN) has been developed and validated.[31] Each of the following independent prognostic factors is given a score of 1:

  • Age >40 years

  • Heart rate >120 beats per minute

  • Cancer or hematologic malignancy

  • Involved body surface area >10%

  • Blood urea nitrogen level >10 mmol/L (28 mg/dL)

  • Serum bicarbonate level < 20 mmol/L (20 mEq/L)

  • Blood glucose level >14 mmol/L (252 mg/dL)

The number of positive criteria and the corresponding mortality rates are as follows:

  • 0: 1 to 3%

  • 2: 12%

  • 3: 35%

  • 4: 58%

  • 5 or more: 90%

Sequelae

Major sequelae are generally limited to the affected organ systems (ie, the skin and mucosal membranes).

Cutaneous sequelae of TEN include the following:

  • Changes in skin pigment (hypopigmentation or hyperpigmentation; sun exposure must be avoided for several months because ultraviolet light can worsen hyperpigmentation; sunblock is recommended)

  • Nail loss and nail dystrophy

  • Hypohidrosis (inability to sweat)

  • Scarring, alopecia, and hypertrophic scarring

  • Dermal desiccation, causing deep dermal wounds

  • Chronic xerostomia

  • Esophageal strictures

  • Vulvovaginal synechiae

  • Phimosis

  • Chronic erosion of the mouth and genitalia

Ocular complications generally result from abnormal keratinization of the tarsal conjunctiva. A Sjogrenlike syndrome with decreased lacrimal secretion causes dry eye and predisposes to corneal abrasions and corneal scarring with neovascularization. In addition, patients have been reported to have palpebral synechiae, entropion, or symblepharon (adhesion of the eyelids).[32]

A study by Power and colleagues found that 50% of patients with TEN developed ocular complications.[33] Patients treated with steroids fared no better than those treated without steroids. Therefore, TEN remains a common cause of visual loss in a significant number of patients. Ultimately, 5-9% of patients can become blind as a result of some of these complications.

Up to 28% of women with vaginal involvement in the acute phase suffered from long-term sequelae, including burning sensation, dyspareunia, and postcoital bleeding from adhesions and stenosis. Male genitalia synechiae may require circumcision.[34]

 

Presentation

History

Patients with toxic epidermal necrolysis (TEN) may describe an influenzalike prodrome characterized by the following:

  • Malaise

  • Rash

  • Fever

  • Cough

  • Arthralgia

  • Myalgia

  • Rhinitis

  • Headache

  • Anorexia

  • Nausea and vomiting, with or without diarrhea

Other prodromal signs and symptoms include conjunctivitis (32%), pharyngitis (25%), and pruritus (28%). The prodrome typically lasts from 1 day to as long as 3 weeks.

The cutaneous eruption begins as a poorly defined, erythematous macular rash with purpuric centers. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment. The lesions predominate on the torso and face, sparing the scalp. Pain at the site of the skin lesions is often the predominating symptom and is often out of proportion to physical findings in early disease.

Mucous membrane erosions (seen in 90% of cases) generally precede the skin lesions by 1-3 days. The most frequently affected mucosal membrane is the oropharynx, followed by the eyes and genitalia. Oral cavity involvement typically presents as a sore or burning sensation. Intake may be limited because of pain associated with the oropharyngeal lesions.

Ocular manifestations range from acute conjunctivitis to corneal erosions and ulcers. Genital involvement may result in painful urination. Other mucosal surfaces such as the esophagus, intestinal tract, or respiratory epithelium may be affected. Bronchial epithelial sloughing may result in dyspnea and hypoxemia.

Gastrointestinal involvement is extremely rare and involves colonic mucosa, esophageal mucosa, ileal mucosa, and diffuse gastrointestinal involvement.[35]

Most cases of TEN are drug induced, typically occurring within 1-3 weeks of therapy initiation and rarely occurring after more than 8 weeks. Therefore, a detailed medication history, focusing on medications that have been recently started, is a vital component of the patient's history.

More than 220 different medications have been suggested. The most commonly implicated agents include the following:

  • Sulfonamide antibiotics

  • Antiepileptic drugs

  • Oxicam nonsteroidal anti-inflammatory drugs

  • Allopurinol

  • Nevirapine

  • Abacavir

  • Lamotrigine

Fewer than 5% of patients report no history of medication use.

Physical Examination

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. The skin lesions coalesce and fill with fluid-producing large, flaccid blisters. The epidermis sloughs in sheets, leaving a characteristic moist, denuded dermis. Conjunctivitis and denudation and erosions of other mucous membranes precede epidermal necrolysis.

Epidermal sloughing in toxic epidermal necrolysis Epidermal sloughing in toxic epidermal necrolysis (TEN).
Toxic epidermal necrolysis (TEN) ulcer in great to Toxic epidermal necrolysis (TEN) ulcer in great toe (initial infection).

A positive Nikolsky sign is evident when the application of slight lateral pressure to the epidermal surface results in the epidermis easily separating from its underlying surface.

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.

Involvement of the oral mucosa results in edema and erythema, followed by blistering. Ruptured blisters may form extensive hemorrhagic erosions with grayish white pseudomembranes or shallow aphthouslike ulcers. Hemorrhagic crusting of the lips is a common finding.

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

Ocular involvement varies in severity and can result in mild inflammation, conjunctival erosion, purulent exudates, or pseudomembrane formation.

Involvement of respiratory epithelium may result in bronchial hypersecretion, hypoxemia, interstitial infiltrates, pulmonary edema, bacterial pneumonia, or bronchiolitis obliterans.

Complications

Numerous complications of TEN can arise as a result of the widespread cutaneous and mucosal membrane inflammation and necrosis. Stomatitis and mucositis, which are painful and hinder oral intake, can place patients at risk for dehydration and malnutrition.

Epithelial loss predisposes to septicemia (Pseudomonas aeruginosa, Staphylococcus aureus, gram-negative species, and Candida albicans). Renal hypoperfusion, acute tubular necrosis, and renal insufficiency may develop subsequent to septic shock.

Ulceration of various mucosal membranes may result in pain, scarring, and stricture formation. Affected surfaces include oral, ocular, and urogenital mucosa. Barrera and colleagues reported a case of hypopharyngeal stenosis and dysphagia with recurrent aspiration.[36] Miscellaneous complications include hypovolemia, massive gut bleeding, and pulmonary emboli.

Mild-to-severe eye complications can occur, such as the following:

  • Lid edema
  • Persistent dry eyes
  • Chronic photosensitivity
  • Conjunctivitis
  • Keratitis
  • Conjunctival fornix foreshortening
  • Ectropion or  entropion with subsequent  trichiasis
  • Symblepharon
  • Anklyoblepharon
  • Corneal ulceration,scarring or neovascularization
  • Blindness
  • Bronchiolitis obliterans

Pulmonary complications may occur. Mucous retention and sloughing of tracheobronchial mucosa may occur, with aspiration of mucosal debris. Pneumonia and pneumonitis are common and sometimes fatal complications of TEN. Pulmonary embolism and acute respiratory distress syndrome (ARDS) have also been reported.

GI hemorrhage results from intestinal inflammation.

Buccal and dental complications include gingival synechiae, gingival recession, dental alteration, xerostomia and increased saliva acidity.

 

DDx

Diagnostic Considerations

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are considered to be a single disease entity differing in severity. There is debate whether TEN and SJS are part of a spectrum of disorders including erythema multiforme major (EMM); however, it is widely accepted that SJS and TEN are distinct entities differing in etiology, clinical manifestations, histopathology, treatment, and prognosis.

EMM is characterized by typical target lesions (at least 3 concentric rings) with or without blister formation in a symmetric, predominantly acral distribution. In contrast, the skin lesions of SJS and TEN are predominately central (trunk and face), consisting of blisters that arise on erythematous or purpuric macules and involve 2 or more mucosal surfaces.

Histopathologic examination is necessary in differentiating these disorders from other severe bullous skin diseases, including the following[37] :

TEN and SJS are characterized by apoptotic keratinocyte cell death in the epidermis with dermal-epidermal separation that results in bullae formation.

Other problems to be considered in the differential diagnosis of TEN include the following:

  • Cauterization burns
  • Caustic agents
  • Drug reaction with eosinophilia
  • Generalized pustular figurate erythema [39, 40] ; sometimes seen with pustulosis and atypical targetoid erythema multiforme-like plaques with cutaneous sloughing and excoriations with blisters or erosions that may suggest TEN.
  • Generalized bullous fixed eruption [41]
  • Kerosene and paraffin burns

Differential Diagnoses

 

Workup

Approach Considerations

TEN is a clinical diagnosis, confirmed by histopathologic analysis of lesional skin. Early involvement of a dermatologist and dermatopathologist is recommended. Skin biopsy, harvested at the earliest possible stage, is important in establishing an accurate diagnosis and directing specific therapeutic modalities.

Necrotic keratinocytes with full-thickness epithelial necrosis and detachment is consistent with the diagnosis of TEN. Perivascular and scattered lymphocytic infiltration of the dermis is sometimes demonstrated, although the underlying dermis is not greatly altered.

No definitive or specific emergent laboratory tests are indicated for TEN. Basic laboratory tests may be helpful in planning symptomatic or supportive therapy. Surveillance cultures of blood, skin, and urine should be obtained.

Imaging studies are not indicated for the diagnosis of TEN. Chest radiography should be performed in the setting of respiratory distress because tracheobronchial inflammation may predispose to diffuse interstitial pulmonary disease or pneumonia.

Blood Studies

Hematology studies include the following:

  • Complete blood count (CBC) and differential

  • Circulating immune complexes

  • Erythrocyte sedimentation rate

Leukopenia is common, whether a result of TEN itself or of bacteremia, as is a normochromic normocytic anemia. Eosinophilia may be present. Less often, thrombocytopenia, neutropenia, and bandemia may occur. Neutropenia is an unfavorable prognostic sign.

In the acute phase, there are transient decreases of peripheral CD4+ T lymphocytes and reduced allogeneic and natural killer cell cytotoxicity, which returns to normal in 7-10 days.

Coagulation studies may include prothrombin time/international normalized ratio (INR) and activated partial thromboplastin time.

Chemistry to assess fluid and electrolyte losses include the following:

  • Albumin

  • Blood urea nitrogen

  • Total protein

As toxic epidermal necrolysis progresses, multiple organs are affected, causing other abnormalities in laboratory test results. Diffuse skin involvement may cause significant fluid loss and electrolyte abnormalities.

Biopsy

A skin biopsy specimen must be obtained. In experienced hands, a frozen section specimen expedites matters. Results are very useful in differentiating TEN from other dermatologic disorders.

Histologically, TEN is characterized by full-thickness epidermal necrosis with little evidence of epidermal or dermal inflammation. Epidermal detachment and sloughing may be evident. Satellite cell necrosis may be visible early, progressing to extensive eosinophilic necrosis.

Other Tests

Patch testing may be used to identify the culprit drugs.[42]  Patch tests show an acceptable sensitivity, yielding positive results in 50% of patients with acute generalized exanthematous pustulosis and in 50% of patients with maculopapular exanthema.

 

Treatment

Approach Considerations

Management of toxic epidermal necrolysis (TEN) requires prompt recognition of the disorder and withdrawal of all potential causative agents. The mainstay of treatment is supportive care until the epithelium regenerates. Supportive measures include isolation, fluid and electrolyte balance, nutritional support, pain management, and protective dressings. Early transfer of patients to a burn or intensive care unit has been shown to reduce the risk of infection, mortality rate, and length of hospitalization.

Withdraw the offending agent, if one is identified, as soon as possible. One observational study showed a reduction in mortality from 26% to 5% when the implicated drugs with short elimination half-lives were withdrawn no later than the day the blisters or erosions first developed.

No controlled prospective treatment studies or generally accepted guidelines exist. In 1991, Avakian and colleagues published the University of Florida treatment protocol for toxic epidermal necrolysis.[43] In 2007, these guidelines were revised by Fromowitz and colleagues.[44] The guidelines are as follows:

Monitor fluids and electrolytes. Administer fluids and titrate based on central venous pressure and urine output; on average, 3-4 L are needed in patients with 50% of the body surface area affected.

 

Prehospital Care

Prehospital care for patients with TEN is similar to that for patients with burns. Supplement with oxygen by face-mask as needed; do not perform prophylactic tracheal intubation. Prevent hypothermia with rewarming devices and blankets.

In severe TEN, the barrier function of the skin is compromised. Thus, contamination and evaporation must be minimized. The patient should be treated similarly to one with extensive burns, that is, with the application of sterile coverings. Fluid and pulmonary status must be carefully monitored.

Emergency Department Care

For the emergency physician, the two most important elements in the treatment of TEN are discontinuation of the offending drug and admission to a burn unit.[45] Evidence suggests that rapid institution of these two measures is associated with a more favorable prognosis.[46, 47]

Emergency department care should be directed toward the following:

  • Maintaining fluid and electrolyte homeostasis

  • Mitigating temperature loss-the patient’s room should be heated to a temperature of 25OC-28 OC.[48]

  • Providing adequate analgesia

  • Preventing secondary infection

Aggressive fluid and electrolyte management, pain control, and meticulous skin care are important. Fluid resuscitation with crystalloids should follow standard guidelines used for burn patients. However, patients with TEN typically require less aggressive fluid replacement than that of burn patients because of less severe microvascular injury.

A goal of resuscitation should be to maintain sufficient mean arterial blood pressure (ABP >65 mm Hg), central venous pressure (CVP 8-12 mm Hg), and central oxygenation (Svco2 >70%) for adequate tissue perfusion and renal perfusion.[27] Fluid management should be based on the physiologic endpoint of urine output of 0.5-1 mL/kg/h.[45]

Patients with extensive skin involvement require reverse isolation and a sterile environment. Areas of skin erosion should be covered with nonadherent protective dressings such as petrolatum gauze. Respiratory distress may result from mucosal sloughing and edema and may necessitate endotracheal intubation and ventilation.

Supportive Systemic Therapy

Due to the need for large volume fluid resuscitation and to allow for intravenous medication administration, a large bore intravenous catheter should be placed on a nonerythematous portion of the patient’s body.

The patient should be placed in a heated environment to enhance reepithelialization. However, this may enhance water losses, and appropriate hydration must be maintained. Institute a bed warmer.

Saline applied to skin hourly is important, and then emollients are smeared. Chlorhexidine solution is used to bathe the patient's skin. Chlorhexidine mouthwash is administered 4 times a day, and white petrolatum is administered to the lips. Rinse the patient’s mouth frequently and apply a topical anesthetic or spray for buccal pain.

Provide daily physical therapy for range-of-motion exercises.

Place a Foley catheter and nasogastric tube only when needed. A urinary catheter should be placed in patients with urogenital involvement to decrease the risk of both infection and added injury.[48]

Energy requirements for patients with TEN must be carefully calculated and nutritional support provided. Protein loss can be significant.[30] Enteral nutrition through a nasogastric or naso jejnual tube is preferred to parenteral nutrition when oral mucosal involvement is severe, at 20-25 kcal/kg/day.

Patients with mucosal vulnerability may have severe bleeding complications. Coagulation factors and blood counts should be held within the normal ranges, and transfusion of red cells, platelets, and plasma products should be considered when necessary.[27]

Ocular complications are common and can be debilitating. Early consultation with an ophthalmologist is recommended to assess and minimize the risk of ocular damage. Treatments with topical lubricants/antibiotics and steroid drops are often needed.

Wound care

Meticulous wound care is necessary to prevent secondary infection. Debate continues in the literature regarding whether or not to debride the wounds associated with toxic epidermal necrolysis. To date, no conclusive evidence supports early, late, or no debridement of the wounds. Cutaneous lesions heal in approximately 2 weeks; mucosal membrane lesions take longer.

If debridement of necrotic and desquamation areas is chosen, it is performed with the patient under general anesthesia. Apply porcine xenografts to involved areas.

Provide hydrotherapy (whirlpool) twice a day. Repair and replace porcine xenografts. Apply Kerlix dressings soaked in silver nitrate 0.5% to involved areas after each whirlpool session.

Collagen dressings have been found to inhibit the action of metalloproteinases and encourage wound healing through deposition and organization of freshly formed fibers and granulation tissue in the wound bed, creating a good environment for wound healing.[49]

Pharmacologic therapies

Emergence of resistance precludes the use of prophylactic antibiotics. Bacterial sampling of skin lesions should be performed the first day and every 48 hours. Indicators for antibiotic treatment include increased number of bacteria cultured from the skin with selection of a single strain, sudden decrease in temperature, or deterioration of the patient's condition.

Empiric antimicrobial therapy should include broad-spectrum antimicrobials that cover gram-negative, gram-positive, and anaerobic organisms. Staphylococcus aureus is the main bacteria present during the first days, with gram-negative strains appearing later. If staphylococcal infection is involved, administer an appropriate antistaphylococcal agent (ie, nafcillin/oxacillin for methicillin-sensitive organisms or vancomycin for methicillin-resistant organisms).

Provide pain relief with patient-controlled analgesia (PCA). Opiate analgesics for skin pain and anxiety are essential for comforting patients. Hydroxyzine may be used to relieve the intense pruritus that may occur when reepithelialization begins.

Patients remain nonambulatory until skin begins to heal. Until that time, anticoagulant therapy is imperative. Heparin is indicated for prophylaxis of thromboembolic events.

Apply chloramphenicol ointment to prevent infection. Silver sulfadiazine should be avoided because it is a sulfonamide derivative and may precipitate TEN. Silver compounds not utilizing sulfadiazine or other sulfa medications should be used because they assist in wound healing and prevent infection and bacterial growth.

No specific treatment modality has been proven effective, including the following:

  • Plasmapheresis

  • Corticosteroids

  • Cyclophosphamide

  • Cyclosporine

  • Tumor necrosis factor–alpha (TNF-alpha) inhibitors

  • Intravenous immune globulin (IVIg)[7, 50]

Multiple studies of these modalities have been completed, and multiple studies are ongoing. Completed studies have shown that either the risk of the medication outweighs the benefit or the data are inconclusive to support its utilization. Therefore, there is a significant need for randomized control studies to further evaluate potential treatment modalities in TEN.

Corticosteroids are commonly used to control progression of TEN, but this is highly controversial. In some studies, corticosteroids have increased the incidence of mortality.

Consider the use of plasmapheresis, if available, daily for 3 days. Although prospective randomized studies have not been performed, limited data suggest that plasmapheresis may enhance elimination of the drug or offending agent or inflammatory mediators such as cytokines and should be considered.[51]

Anti–TNF-α treatment has been reported to rapidly resolve skin lesions due to TEN. TNF-α is strongly expressed in keratinocytes and macrophages of lesional skin, and high concentrations are found in cutaneous blister fluid.

Sucrose-depleted IVIg 1 g/kg/d (infused over 4 h) for 3 days may be beneficial if started within 48-72 hours of bulla onset. If more than 72 hours have elapsed since the onset of bulla but TEN is still actively progressing, with new lesions, IVIg may still be useful.

TEN patients with neutropenia tend to have a poor prognosis due to their increased risk of developing an infection. In these patients, granulocyte colony-stimulating factor may be beneficial.[52]

Menstrual suppression may reduce the risk of vaginal adenosis and endometriosis and can be considered in patients with severe genital mucosal involvement. Topical estrogen has been shown to promote healing in other vulvular dermatoses and burns and should be considered as adjuvant therapy.[53]

Consultations

Most patients with TEN require specialized care under the direction of a team of physicians with experience in handling this disorder. Burn-unit care represents an option worthy of serious consideration.

Required consultations may include the following:

  • A dermatologist is consulted to identify and to confirm the diagnosis of TEN

  • A plastic surgeon is consulted to debride areas of skin necrosis, as indicated

  • An ophthalmologist is consulted for assisting in the treatment of ocular manifestations and preventing long-term sequelae

  • An internal medicine specialist is consulted to assist in patient treatment

  • Consultation with a respiratory medicine specialist may be important, since respiratory mucosa may slough; establishment of pulmonary toilet may be advisable

  • Otolaryngologic or urologic consultation may be helpful in patients with significant mucous membrane involvement of those areas.

Diet

Parenteral nutrition or nutrition provided enterally via a soft-fine bore nasogastric tube is usually needed. Start total parenteral nutrition in patients unable to take nourishment. Early and continuous enteral nutrition reduces the risk of stress ulcers, reduces bacterial translocation and enterogenic infection, and allows earlier discontinuation of venous lines.[54]

Activity

Encourage mobilization. Involve physiotherapy for mobilization, those needing respiratory support and in those who are immobile and in need of passive exercises.[55]

Prevention

There are currently no guidelines to prevent or minimize the risk of re-exposure in patients diagnosed with TEN. In the inpatient setting, when a diagnosis is made, the medical record should be updated to reflect the diagnosis in the allergies section with the severity categorized as critical. Prior to discharge, the diagnosis and implicated drugs/classes should be discussed with the patient and a plan for preventing re-exposure should be developed. The diagnosis should be communicated to the patient’s pharmacy and physicians. Medical identification jewelry should be obtained which include the brand and generic names of the allergen. Family members of TEN patients may be susceptible to the same drugs and should be counseled to avoid these medications when possible.[52, 56]

Long-Term Monitoring

Long-term gynecology care is recommended.

Pulmonary function tests performed during the usual follow-up display abnormalities presenting mainly as asymptomatic diffusion impairment, with a risk proportional to BSA involvement.

 

Guidelines

Guidelines Summary

Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults[53]

Guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis: An Indian perspective[57]

British Association of Dermatologists’ guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in children and young people, 2018[55]

 

Medication

Medication Summary

The goals of pharmacotherapy in toxic epidermal necrolysis (TEN) are to reduce morbidity and to prevent complications. No specific treatment modality has been proven effective, but agents such as crystalloids, antibiotics, antihistamines, anticoagulants, analgesics, and antiseptic agents are important for supportive care. Use of corticosteroids is controversial.

Crystalloids

Class Summary

Fluid resuscitation is critical in TEN. In cases of acute skin failure, insensible losses may be enormous, and repletion of water loss is essential.

Isotonic sodium chloride 0.9%

Patients with TEN are at serious risk of dehydration, which may complicate their condition. For example, water losses in a hypercatabolic state result in hypoalbuminemia and reduced renal perfusion. This leads to acute renal failure; therefore, maintaining intravascular volume is paramount. The rate of intravenous repletion should be titrated based on urine output or central venous pressure.

Antibiotics

Class Summary

Patients with TEN lose their epidermis, a major barrier to invading organisms. If patients become infected, morbidity is enhanced. Staphylococcus aureus is the main bacterium present during the first days, with gram-negative strains appearing later.

Case reports of Klebsiella species,[58] Escherichia coli, and Pseudomonas species recovered from patients with TEN have created concern about the possible polymicrobial nature of sepsis associated with this condition. Therefore, good gram-negative coverage may be necessary.

Nafcillin

Nafcillin covers most common skin organisms (eg, Staphylococcus, Streptococcus). If patient has allergy to penicillin or if methicillin-resistant S aureus (MRSA) is present on skin culture, use vancomycin.

Gentamicin

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Third-generation cephalosporins, such as ceftazidime, and others with good gram-negative coverage are suitable alternatives. Adjust dose based on renal insufficiency.

Antihistamines

Class Summary

Hydroxyzine may be used when reepithelialization begins because intense pruritus may occur.

Hydroxyzine (Vistaril)

Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in subcortical region of the central nervous system.

Anticoagulants

Class Summary

Heparin is indicated for prophylaxis of thromboembolic events. Patients with TEN remain nonambulatory until skin begins to heal, and until that time, anticoagulant therapy is imperative.

Heparin

Heparin augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse thrombus but is able to inhibit further thrombogenesis. Heparin prevents reaccumulation of clot after spontaneous fibrinolysis. It is indicated for the prevention of thromboembolic events.

Analgesics

Class Summary

Opiate analgesics are important to alleviate pain and anxiety associated with TEN. Much like treatment of a second-degree burn, the pain must not be ignored.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

Morphine is the drug of choice for pain in patients with TEN. In case of allergy or intolerability, fentanyl may be used.

Fentanyl Citrate ( Fentora, Abastral, Duragesic)

A synthetic opioid analgesic that is primarily a mu receptor agonist, fentanyl is 50-100 times more potent than morphine. It has short duration of action (1-2 h) and minimal cardiovascular effects, such as hypotension. Respiratory depression is uncommon, but this effect lasts longer than its analgesic effect. Fentanyl is frequently used in patient-controlled analgesia for relief of pain. Unlike morphine, fentanyl is not commonly associated with histamine release.

Antiseptics

Class Summary

These agents inhibit growth of gram-positive and gram-negative bacteria.

Chlorhexidine gluconate (PerioGard, Peridex, Hibiclens, Avagard)

Chlorhexidine binds to negatively charged bacterial cell walls and extramicrobial complexes. It has bacteriostatic and bactericidal effects.

Topical Anesthetics

Class Summary

Topical anesthetics can be applied to mucous membranes, especially buccal, to relieve pain.

Benzocaine (Americaine, Anbesol, Chiggerex Plus)

Benzocaine inhibits neuronal membrane depolarization, blocking nerve impulses. It provides oral or mucosal anesthesia, thereby controlling pain.

Corticosteroids

Class Summary

While corticosteroids may be used, their use is highly controversial. Although high-dose corticosteroids used early in the course of TEN (within 24-48 hours of onset) may halt the progression of the reaction, many experts believe that corticosteroids should not be used because they predispose patients to infection, mask early signs of sepsis, encourage GI bleeding, and impair or delay wound healing.

If corticosteroids are used, the initial high dose is titrated down as quickly as possible and tapered off, usually over 7-10 days.

Dexamethasone (Baycadron)

Dexamethasone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Other corticosteroids, such as methylprednisolone, prednisone, and hydrocortisone, also may be used.

Methylprednisolone (Solu-Medrol, Medrol, A-Methapred)

Methylprednisolone is a highly potent synthetic glucocorticoid that causes diverse metabolic effects and modifies the body's immune responses to various stimuli.

Prednisone

Prednisone, a synthetic glucocorticoid analog, acts as a potent immunosuppressant. It May inhibit cyclooxygenase, which, in turn, inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.

Hydrocortisone (A-Hydrocort, Solu-Cortef, Cortef)

Hydrocortisone elicits anti-inflammatory properties and causes profound and varied metabolic effects. This agent modifies the body's immune response to diverse stimuli.

 

Questions & Answers

Overview

What is toxic epidermal necrolysis (TEN)?

What causes toxic epidermal necrolysis (TEN)?

What is the role of Stevens-Johnson syndrome (SJS) in the etiology of toxic epidermal necrolysis (TEN)?

How is toxic epidermal necrolysis (TEN) classified?

How is toxic epidermal necrolysis (TEN) with spots defined?

How is toxic epidermal necrolysis (TEN) without spots defined?

How is Overlap Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) defined?

How is toxic epidermal necrolysis (TEN) diagnosed and treated?

How is toxic epidermal necrolysis (TEN) differentiated from staphylococcal scalded skin syndrome?

What should be included in patient education for toxic epidermal necrolysis (TEN)?

What is the pathophysiology of toxic epidermal necrolysis (TEN)?

How does toxic epidermal necrolysis (TEN) mimic a hypersensitivity reaction?

What causes widespread epidermolysis and blistering in toxic epidermal necrolysis (TEN)?

Which immunopathologic pathways are involved in the pathogenesis of toxic epidermal necrolysis (TEN)?

What causes toxic epidermal necrolysis (TEN)?

Which antibacterial drugs cause toxic epidermal necrolysis (TEN)?

Which anticonvulsants cause toxic epidermal necrolysis (TEN)?

Which NSAIDS cause toxic epidermal necrolysis (TEN)?

How does the risk of allopurinol-induced toxic epidermal necrolysis (TEN) vary over time?

Which lab tests are used to confirm specific drug etiologies for toxic epidermal necrolysis (TEN)?

What are non-pharmacological etiologies of toxic epidermal necrolysis (TEN)?

What is the incidence of toxic epidermal necrolysis (TEN) in the US?

What is the global incidence of toxic epidermal necrolysis (TEN)?

What are the racial predilections for toxic epidermal necrolysis (TEN)?

How does the prevalence of toxic epidermal necrolysis (TEN) vary by sex?

How does the incidence of toxic epidermal necrolysis (TEN) vary by age?

What is the mortality rate for toxic epidermal necrolysis (TEN)?

What are the most common causes of mortality in toxic epidermal necrolysis (TEN)?

What are the most important negative prognostic factors for toxic epidermal necrolysis (TEN)?

Which factors are associated with a poor prognosis of toxic epidermal necrolysis (TEN)?

How is the toxic epidermal necrolysis prognostic score (SCORTEN) calculated?

How is SCORTEN used to predict mortality in toxic epidermal necrolysis (TEN)?

Which organ systems are affected by toxic epidermal necrolysis (TEN)?

What are the cutaneous sequelae of toxic epidermal necrolysis (TEN)?

What are the ocular complications of toxic epidermal necrolysis (TEN)?

Presentation

What are the prodromal signs and symptoms of toxic epidermal necrolysis (TEN)?

How are the cutaneous eruptions characterized in toxic epidermal necrolysis (TEN)?

What are the manifestations of mucous membrane erosions in toxic epidermal necrolysis (TEN)?

What are the ocular manifestations in toxic epidermal necrolysis (TEN)?

What is the importance of a detailed medication history in the evaluation of toxic epidermal necrolysis (TEN)?

What are the most commonly implicated medications involved in toxic epidermal necrolysis (TEN)?

What are the vital signs findings suggestive of toxic epidermal necrolysis (TEN)?

Which skin exam findings are characteristic of toxic epidermal necrolysis (TEN)?

What is a positive Nikolsky sign in toxic epidermal necrolysis (TEN)?

What is the progression of erythema in patients with toxic epidermal necrolysis (TEN)?

What are the oral mucosa findings characteristic of toxic epidermal necrolysis (TEN)?

What are the ocular findings characteristic of toxic epidermal necrolysis (TEN)?

What are the respiratory findings characteristic of toxic epidermal necrolysis (TEN)?

What are the common causes of complications in toxic epidermal necrolysis (TEN)?

What causes septicemia and septic shock in toxic epidermal necrolysis (TEN)?

What may result from ulceration of mucosal membranes in toxic epidermal necrolysis (TEN)?

What are the possible ocular complications of toxic epidermal necrolysis (TEN)?

What are the pulmonary complications of toxic epidermal necrolysis (TEN)?

What are the GI complications of toxic epidermal necrolysis (TEN)?

DDX

What is the relationship of erythema multiforme major (EMM) to toxic epidermal necrolysis (TEN)?

How is erythema multiforme major (EMM) differentiated from toxic epidermal necrolysis (TEN)?

Which disorders must be histologically differentiated from toxic epidermal necrolysis (TEN)?

How are toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) differentiated?

Which conditions should be included in the differential diagnoses of toxic epidermal necrolysis (TEN)?

What are the differential diagnoses for Toxic Epidermal Necrolysis (TEN)?

Workup

How is toxic epidermal necrolysis (TEN) diagnosed?

How are necrotic keratinocytes characterized in toxic epidermal necrolysis (TEN)?

What is the role of lab tests in the workup of toxic epidermal necrolysis (TEN)?

What is the role of imaging studies in the workup of toxic epidermal necrolysis (TEN)?

Which blood studies are performed in the workup of toxic epidermal necrolysis (TEN)?

Which findings on blood studies suggest toxic epidermal necrolysis (TEN)?

Which findings of circulating immune complexes suggest toxic epidermal necrolysis (TEN)?

Which coagulation studies are performed in the workup of toxic epidermal necrolysis (TEN)?

How are fluids and electrolytes assessed in the workup of toxic epidermal necrolysis (TEN)?

What may cause significant fluid loss and electrolyte abnormalities in toxic epidermal necrolysis (TEN)?

What is the role of a skin biopsy in the workup of toxic epidermal necrolysis (TEN)?

Which histological findings are characteristic of toxic epidermal necrolysis (TEN)?

Treatment

What are the treatment options for toxic epidermal necrolysis (TEN)?

How does withdrawal of the inciting agent affect mortality in toxic epidermal necrolysis (TEN)?

What are the treatment guidelines for toxic epidermal necrolysis (TEN)?

What is included in prehospital care for toxic epidermal necrolysis (TEN)?

What is included in prehospital care of severe toxic epidermal necrolysis (TEN)?

What are the most important elements of emergency department (ED) treatment of toxic epidermal necrolysis (TEN)?

What should be the focus of emergency department (ED) care for toxic epidermal necrolysis (TEN)?

Which guidelines should be followed for fluid resuscitation in toxic epidermal necrolysis (TEN)?

What is the goal of resuscitation for toxic epidermal necrolysis (TEN) in the emergency department (ED)?

How is extensive skin involvement in toxic epidermal necrolysis (TEN) managed in the emergency department (ED)?

What are the benefits of anti-tumor necrosis factor–alpha (TNF-alpha) inhibitors in the treatment of toxic epidermal necrolysis (TEN)?

What is included in supportive systemic therapy for toxic epidermal necrolysis (TEN)?

How is bleeding managed in toxic epidermal necrolysis (TEN)?

How are ocular complication managed in toxic epidermal necrolysis (TEN)?

How is wound care provided in the treatment of toxic epidermal necrolysis (TEN)?

How is debridement of necrotic and desquamation areas performed in the treatment of toxic epidermal necrolysis (TEN)?

What is the role of antibiotics in the treatment of toxic epidermal necrolysis (TEN)?

What is the role of empiric antimicrobial therapy in the treatment of toxic epidermal necrolysis (TEN)?

How is pain managed in toxic epidermal necrolysis (TEN)?

What is the role of anticoagulant therapy in the treatment of toxic epidermal necrolysis (TEN)?

How are infections prevented in toxic epidermal necrolysis (TEN)?

Which treatments are effective for toxic epidermal necrolysis (TEN)?

What have studies shown regarding the benefits of using medications to treat toxic epidermal necrolysis (TEN)?

What are the risks of corticosteroids to treat toxic epidermal necrolysis (TEN)?

What is the role of plasmapheresis in the treatment of toxic epidermal necrolysis (TEN)?

What is the role of sucrose-depleted IV immune globulin (IVIg) in the treatment of toxic epidermal necrolysis (TEN)?

Which specialist consultations are required for the treatment of toxic epidermal necrolysis (TEN)?

Medications

What is the role of medication in the treatment of toxic epidermal necrolysis (TEN)?

Which medications in the drug class Corticosteroids are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Topical Anesthetics are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Antiseptics are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Analgesics are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Anticoagulants are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Antihistamines are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Antibiotics are used in the treatment of Toxic Epidermal Necrolysis (TEN)?

Which medications in the drug class Crystalloids are used in the treatment of Toxic Epidermal Necrolysis (TEN)?