BASICS
A severe T-cell " “mediated immunologic reaction resulting in extensive epidermal detachment that requires immediate drug withdrawal (if inciting medication present) and admission to a burn/ICU unit ‚
DESCRIPTION
- Toxic epidermal necrolysis (TEN) is a severe dermatologic condition marked clinically by extensive epidermal detachment of skin and mucous membranes.
- On the same spectrum as Stevens-Johnson syndrome (SJS) with TEN defined as >30% body surface area (BSA) epidermal detachment. SJS is <10% BSA involvement, whereas SJS/TEN overlap is 10 " “30% BSA involvement.
- Most often the result of an adverse drug reaction: secondary to inappropriate immune response/activation to drug or drug metabolites
- System(s) affected: skin/mucosa, respiratory, gastrointestinal (GI), genitourinary, ocular involvement
- Synonym(s): toxic erythema necrosis; Lyell syndrome (1)
EPIDEMIOLOGY
Incidence
- Incidence of 0.4 to 1.9 cases per million per year worldwide; with the highest incidence in Africa, Asia, and India
- Affects all ages; males and females are affected equally.
- Special consideration in the geriatric population, immunosuppressed and HIV patients (risk 1:1,000), and those with malignancy
- The risk of mortality increases with surface area involved and meta-analyses of the literature shows the risk to be between 16 " “55% (2).
ETIOLOGY AND PATHOPHYSIOLOGY
- TEN is characterized by widespread keratinocyte apoptosis that leads to epidermal detachment from the dermis.
- Pathologic mechanism has not been fully established, although immune mechanisms and altered drug metabolism have been suggested:
- Recognition of offending drug triggers HLA class 1 molecule-initiated CD8+ cytotoxic T-cell activation (CD 8+ T cells). T-cell and natural killer (NK) cell induce damage via perforin/granzyme/granulysin damage or Fas/Fas ligand (FasL) interaction.
- Tumor necrosis factor-α (TNF-α) and reactive nitric oxide have also been implicated in keratinocyte damage (3).
- >80 " “90% of TEN is drug-induced. >100 drugs have been found to cause SJS/TEN. Commonly implicated medications include the following:
- Antibacterial and antifungal agents (sulfonamides, penicillins, cephalosporins, tetracycline, terbinafine)
- Anticonvulsants (hydantoins, barbiturates, carbamazepine, lamotrigine)
- Nonantibiotic sulfonamides (sulfasalazine)
- Analgesics, oxicam-NSAIDs
- Allopurinol
- Nevirapine
Genetics
Certain HLA haplotypes predispose to increased susceptibility to SJS/TEN with particular drug use: ‚
- HLA-B*1502 has been associated with carbamazepine-induced SJS in the Han Chinese population; the FDA recommends genotyping of all Asian patients for HLA-B*1502 before initiating carbamazepine treatment.
- HLA-B*5801 has been linked to allopurinol-induced SJS. HLA-B85701, HLADR7, and HLA-DQ3 are associated with abacavir-induced hypersensitivity.
- HLA-A*0206 and HLA-B12 may be a marker of increased ocular complications in SJS/TEN in Japanese and Caucasian patients, respectively (1).
RISK FACTORS
- Immunosuppression, including HIV/AIDS, specific HLA haplotypes, and malignancy (1)
- Multiple concurrent medications increase risk.
GENERAL PREVENTION
- Always ask patients about prior adverse drug events.
- Be aware of medications with higher incidence of cutaneous drug reactions.
DIAGNOSIS
HISTORY
- Onset is typically 1 to 3 weeks after initiation of drug.
- Prodrome of fever, malaise, headache, sore throat, and conjunctivitis followed by skin lesions after 1 to 3 days (detailed below in "Physical Exam " ¯)
PHYSICAL EXAM
- Lesions start as painful erythematosus macules followed by development of atypical target lesions with dusky center that progress to vesicles and bullae with surrounding erythema:
- Vesicles coalesce, forming flaccid bullae that slough and result in full-thickness epidermal necrosis/detachment
- Start on face and trunk but spread to include palms and soles.
- Positive Nikolsky sign: Gentle lateral pressure causes epidermal separation.
- Positive Asboe-Hansen sign: movement of a blister with direct pressure to unblistered skin
- Involvement of the eyes, oral, and genital mucosa are often seen.
DIFFERENTIAL DIAGNOSIS
Erythema multiforme and staphylococcal scalded skin syndrome (SSSS) can resemble TEN. Bullous formation in TEN can appear similar to blistering diseases, including pemphigus (4). ‚
DIAGNOSTIC TESTS & INTERPRETATION
- TEN is mostly diagnosed clinically and confirmed by histopathology of skin lesions.
- No specific lab tests
- Anemia, leukopenia, thrombocytopenia, neutropenia may be present; elevated BUN, erythrocyte sedimentation rate (ESR), and transaminases
- Granulysin, a cytotoxic molecule, has been found in blister cells in TEN patients but not in patients with similar skin disorders such as erythema multiforme. It can be detected via ELISA and has been shown to have high specificity for TEN. However, a commercial test is yet to be available (4).
- SCORTEN:
- Validated TEN-specific severity of illness score based on the following variables evaluated during first 24 hours of hospital admission. Each factor assigned 1 point:
- Age ≥40 years
- Presence of malignancy
- Detached BSA ≥10%
- Tachycardia ≥120/min
- Serum urea >10 mmol/L
- Serum glucose >14 mmol/L
- Serum bicarbonate <20 mmol/L
- Score of 0 to 1 has a predictive mortality of 3.2%, whereas score of ≥5 has mortality of 90% (5)[B].
- Serum bicarbonate <20 is the most important negative prognostic factor with an increase in mortality of 40 times in one study (6)[B].
Test Interpretation
- Evaluation of skin biopsy specimen provides definitive diagnosis.
- H/E and frozen section specimens enable visualization of apoptotic keratinocytes in early lesions and dermoepidermal separation, dermal lymphocytic infiltrate, and widespread epidermal necrosis in late lesions. Dermal infiltrate density and adnexal, follicular, and eccrine gland necrosis on pathology were not associated with worse prognosis.
TREATMENT
- Supportive care is still the mainstay of TEN treatment; withdrawal of offending drug agent, if known, is imperative.
- Early transfer to an ICU/burn unit is critical, as patients can rapidly deteriorate:
- Aggressive management of fluid and electrolyte balance, temperature, prevention and treatment of infection, analgesia, nutrition, and respiratory support. Fluid replacement depends on extent of skin and mucosa involvement and may be 5 to 7 L in the first 24 hours; special consideration in pediatric population
- Antibiotics should be avoided unless a proven infection exists.
- Debate on role of debridement; use of wound dressing on exposed dermis to promote reepithelialization and prevent infection
- Ophthalmologic consult to assess severity of ocular involvement (5)[C]
MEDICATION
- Lack of randomized controlled clinical trials in evaluating efficacy of various treatments
- The data are inconclusive in the role of corticosteroids in the treatment of TEN (7).
- Systemic steroid therapy has been shown in small case series to prevent ocular complications (8)[C]
- IVIG is shown to inhibit Fas " “FasL interaction and cell death in vitro. In humans, IVIG doses >2 g/kg (3 to 4 g/kg total) within 4 days of onset of skin lesions may have earlier cessation of disease progression but no overall effect on mortality except in the pediatric population (9,10)[B].
- There have been multiple small case series studying the effects of systemic steroid therapy and IVIG; however, there are no definitive studies or randomized head to head trials comparing the two therapies (8).
- Anti " “TNF-α agents, cyclosporine, and etanercept have demonstrated benefit in small case series, but controlled studies are needed to define their role in treatment (11)[C],(12)[B],(13)[C].
INPATIENT CONSIDERATIONS
- Transfer to a burn center capable of multidisciplinary care early in course improves outcomes.
- Aggressive management of fluid resuscitation, nutritional supplementation, and wound care
- Ocular complications occur in the majority of patients and may include synechiae, corneal ulcers, xerophthalmia, symblepharon, Meibomian gland dysfunction, panophthalmitis, and blindness (14)[C].
- With severe TEN, patient may have respiratory, GI, hepatic, or renal complications.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Avoidance of inciting drug or drug class in the future
- Monitoring of dermatologic and ocular sequelae
PROGNOSIS
- Skin reepithelialization usually occurs within 1 to 3 weeks after epidermal detachment.
- There may be residual skin and ocular sequelae.
COMPLICATIONS
- Skin sequelae include scarring, hypo- and hyperpigmentation, nail loss, and stricture formation (vaginal, urethral, anal).
- Ocular complications may include persistent xerophthalmia and photophobia with possible corneal opacity.
- Respiratory, GI, and renal complications are not uncommon, and the long-term sequelae of multiple organ dysfunction and complex hospital stays has been shown to decrease the quality of life going forward (15).
REFERENCES
11 Schwartz ‚ RA, McDonough ‚ PH, Lee ‚ BW. Toxic epidermal necrolysis: part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69(2):173.e1 " “173.e13.22 Schulz ‚ JT, Sheridan ‚ RL, Ryan ‚ CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3):199 " “204.33 Viard-Leveugle ‚ I, Gaide ‚ O, Jankovic ‚ D, et al. TNF-α and IFN- ˇ ³ are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis. J Invest Dermatol. 2013;133(2):489 " “498.44 Abe ‚ R. Immunological response in Steven-Johnson syndrome and toxic epidermal necrolysis. J Dermatol. 2015;42(1):42 " “48.55 Firoz ‚ BF, Henning ‚ JS, Zarzabal ‚ LA, et al. Toxic epidermal necrolysis: five years of treatment experience from a burn unit. J Am Acad Dermatol. 2012;67(4):630 " “635.66 Yeong ‚ EK, Lee ‚ CH, Hu ‚ FC, et al. Serum bicarbonate as a marker to predict mortality in toxic epidermal necrolysis. J Intensive Care Med. 2011;26(4):250 " “254.77 Law ‚ EH, Leung ‚ M. Corticosteroids in Stevens-Johnson syndrome/toxic epidermal necrolysis: current evidence and implications for future research. Ann Pharmacother. 2015;49(3):335 " “342.88 Araki ‚ Y, Sotozono ‚ C, Inatomi ‚ T, et al. Successful treatment of Stevens-Johnson syndrome with steroid pulse therapy at disease onset. Am J Ophthalmol. 2009;147(6):1004.e1 " “1011.e1.99 Huang ‚ YC, Li ‚ YC, Chen ‚ TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol. 2012;167(2):424 " “432.1010 Kim ‚ DH, Yoon ‚ KC, Seo ‚ KY, et al. The role of systemic immunomodulatory treatment and prognostic factors on chronic ocular complications in Stevens-Johnson syndrome. Ophthalmology. 2015;122(2):254 " “264.1111 Valeyrie-Allanore ‚ L, Wolkenstein ‚ P, Brochard ‚ L, et al. Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2010;163(4):847 " “853.1212 Kirchhof ‚ MG, Miliszewski ‚ MA, Sikora ‚ S, et al. Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol. 2014;71(5):941 " “947.1313 Paradisi ‚ A, Abeni ‚ D, Bergamo ‚ F, et al. Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol. 2014;71(2):278 " “283.1414 Abela ‚ C, Hartmann ‚ CE, De Leo ‚ A, et al. Toxic epidermal necrolysis (TEN): the Chelsea and Westminster Hospital wound management algorithm. J Plast Reconstr Aesthet Surg. 2014:67(8):1026 " “1032.1515 Saeed ‚ H, Mantagos ‚ IS, Chodosh ‚ J. Complications of Stevens-Johnson syndrome beyond the eye and skin [published online ahead of print April 9, 2015]. Burns.
ADDITIONAL READING
- Valeyrie-Allanore ‚ L, Bastuji-Garin ‚ S, Guen ‚ S, et al. Prognostic value of histologic features of toxic epidermal necrolysis. J Am Acad Dermatol. 2013;68(2):e29 " “e35.
- Velez ‚ NF, Saavedra-Lauzon ‚ AP. Toxic exanthems in the adult population. Am J Med. 2010;123(4):296 " “303.
- Zhu ‚ QY, Ma ‚ L, Luo ‚ XQ, et al. Toxic epidermal necrolysis: performance of SCORTEN and the score-based comparison of the efficacy of corticosteroid therapy and intravenous immunoglobulin combined therapy in China. J Burn Care Res. 2012;33(6):e295 " “e308.
CODES
ICD10
L51.2 Toxic epidermal necrolysis [Lyell] ‚
ICD9
695.15 Toxic epidermal necrolysis ‚
SNOMED
- Lyells toxic epidermal necrolysis, subepidermal type (disorder)
- toxic epidermal necrolysis due to drug (disorder)
- Toxic epidermal necrolysis associated with infection (disorder)
CLINICAL PEARLS
- SJS and TEN are on a spectrum, with TEN the more severe disease.
- Expert care in burn centers improves outcomes.