Toxic epidermal necrolysis

Source: Wikipedia, the free encyclopedia.

Toxic epidermal necrolysis
Other names
pain medication[3]
PrognosisMortality 20–50%[2][3]
Frequency1–2 per million per year (together with SJS)[2]

Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a type of severe

multiple organ failure.[2]

The most common cause is certain medications such as

drug reaction with eosinophilia and systemic symptoms.[5] It is called SJS when less than 10% of the skin is involved and an intermediate form with 10 to 30% involvement.[3] Erythema multiforme (EM) is generally considered a separate condition.[6]

Treatment typically takes place in

corticosteroids may also be used.[3][4] Treatments do not typically change the course of the underlying disease.[3] Together with SJS it affects 1 to 2 persons per million per year.[2] It is more common in females than males.[3] Typical onset is over the age of 40.[3] Skin usually regrows over two to three weeks; however, recovery can take months and most are left with chronic problems.[3][4]

Signs and symptoms

Prodrome

TEN ultimately results in extensive skin involvement with redness, necrosis, and detachment of the top (epidermal) layer of the skin and mucosa. Before these severe findings develop, people often have a flu-like prodrome, with a cough, runny nose, fever, decreased appetite and malaise. A history of drug exposure exists on average 14 days (ranging from 1–4 weeks) prior to the onset of symptoms, but may result as early as 48 hours if it is a reexposure.[8]

Skin findings

Initial skin findings include red-purple, dusky, flat spots known as

large blisters. The affected skin can then become necrotic or sag from the body and peel off in great swaths.[7]

  • Toxic epidermal necrolysis on legs
    Toxic epidermal necrolysis on legs
  • TENS Blisters on day 4
    The emerging blisters on day 4 of an instance of TENs
  • TENS patient back
    The back of a TENs patient on day 10, at the peak of the condition

Mucosal findings

Nearly all people with TEN have oral, eye and genital involvement as well. Painful crusts and erosions may develop on any

nasogastric tube through the nose or a gastric tube directly into the stomach. The eyes can become swollen, crusted, and ulcerated, leading to potential blindness. The most common problem with the eyes is severe conjunctivitis.[10]

Complications

Those who survive the acute phase of TEN often develop long-term complications affecting the skin and eyes. Skin manifestations can include scarring, eruptive

xerosis, subconjunctival fibrosis, trichiasis, decreased visual acuity, and blindness.[12]

Cause

Drug reactions have been reported to cause 80–95% of TEN cases.[6]

The drugs most often implicated in TEN are:

TEN has also been reported to result from infection with

transplantation of bone marrow or organs have also been linked to TEN development.[13][6]

HIV

HIV-positive individuals have 1000 times the risk of developing SJS/TEN compared to the general population. The reason for this increased risk is not clear.[7]

Genetics

Certain genetic factors are associated with increased risk of TEN. For example, certain HLA-types such as, HLA-B*1502,[14] HLA-A*3101,[15] HLA-B*5801,[16] and HLA‐B*57:01[17] have been seen to be linked with TEN development when exposed to specific drugs.

Pathogenesis

The immune system's role in the precise pathogenesis of TEN remains unclear. It appears that a certain type of immune cell (

Keratinocytes are the cells found lower in the epidermis and specialize in holding the surrounding skin cells together. It is theorized that CD8+ immune cells become overactive by stimulation from drugs or drug metabolites. CD8+ T cells then mediate keratinocyte cell death through release of a number of molecules, including perforin, granzyme B, and granulysin. Other agents, including tumor necrosis factor alpha and Fas ligand, also appear to be involved in TEN pathogenesis.[6]

Diagnosis

The diagnosis of TEN is based on both clinical and histologic findings. Early TEN can resemble non-specific drug reactions, so clinicians should maintain a high index of suspicion for TEN. The presence of oral, ocular, and/or genital mucositis is helpful diagnostically, as these findings are present in nearly all patients with TEN. The

Nikolsky sign (a separation of the papillary dermis from the basal layer upon gentle lateral pressure) and the Asboe-Hansen sign (a lateral extension of bullae with pressure) are also helpful diagnostic signs found in patients with TEN.[7]

Given the significant morbidity and mortality from TEN, as well as improvement in outcome from prompt treatment, there is significant interest in the discovery of serum biomarkers for early diagnosis of TEN. Serum granulysin and serum high-mobility group protein B1 (HMGB1) are among a few of the markers being investigated which have shown promise in early research.[7]

Histology

Definitive diagnosis of TEN often requires biopsy confirmation. Histologically, early TEN shows scattered necrotic keratinocytes. In more advanced TEN, full thickness epidermal necrosis is visualized, with a subepidermal split, and scant inflammatory infiltrate in the

papillary dermis. Epidermal necrosis found on histology is a sensitive but nonspecific finding for TEN.[7]

  • Confluent Epidermal Necrosis, low mag
    Confluent Epidermal Necrosis, low mag
  • Confluent Epidermal Necrosis, high mag
    Confluent Epidermal Necrosis, high mag

Differential diagnosis

Treatment

The primary treatment of TEN is discontinuation of the causative factor(s), usually an offending drug, early referral and management in

burn units or intensive care units, supportive management, and nutritional support.[7]

Current literature does not convincingly support use of any adjuvant systemic therapy. Initial interest in

Intravenous immunoglobulin (IVIG) came from research showing that IVIG could inhibit Fas-FasL mediated keratinocyte apoptosis in vitro.[19] Unfortunately, research studies reveal conflicting support for use of IVIG in treatment of TEN.[20] Ability to draw more generalized conclusions from research to date has been limited by lack of controlled trials, and inconsistency in study design in terms of disease severity, IVIG dose, and timing of IVIG administration.[7]
Larger, high quality trials are needed to assess the actual benefit of IVIG in TEN.

Numerous other adjuvant therapies have been tried in TEN including,

corticosteroids, ciclosporin, cyclophosphamide, plasmapheresis, pentoxifylline, acetylcysteine, ulinastatin, infliximab, and granulocyte colony-stimulating factors (if TEN associated-leukopenia exists). There is mixed evidence for use of corticosteroids and scant evidence for the other therapies.[7] A meta-analysis from 2002 concluded that there is no reliable evidence for the treatment of TEN.[21] Thalidomide did not show any benefit and was associated with increased mortality compared with placebo.[21]

Prognosis

The mortality for toxic epidermal necrolysis is 25–30%.

respiratory distress which is either due to pneumonia or damage to the linings of the airway. Microscopic analysis of tissue (especially the degree of dermal mononuclear inflammation and the degree of inflammation in general) can play a role in determining the prognosis of individual cases.[22]

Severity score

The "Severity of Illness Score for Toxic Epidermal Necrolysis" (SCORTEN) is a scoring system developed to assess the severity of TEN and predict mortality in patients with acute TEN.[23]

One point is given for each of the following factors:[12]

  • age >40
  • heart rate >120 beats/minute
  • carrying diagnosis of cancer
  • separation of epidermis on more than ten percent of body surface area (BSA) on day 1.
  • Blood Urea Nitrogen >28 mg/dL
  • Glucose >252 mg/dL (14 mmol/L)
  • Bicarbonate <20mEq/L

Score

  • 0–1: 3.2% mortality
  • 2: 12.2% mortality
  • 3: 35.3% mortality
  • 4: 58.3% mortality
  • ≥5: 90% mortality

Of note, this scoring system is most valuable when used on the first and third day of hospitalization, and it may underestimate mortality in patients with respiratory symptoms.[12]

References

  1. ISBN 978-1-4160-2999-1
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  2. ^ a b c d e f g h i j k l m n "Stevens-Johnson syndrome/toxic epidermal necrolysis". Genetics Home Reference. July 2015. Archived from the original on 27 April 2017. Retrieved 26 April 2017.
  3. ^ a b c d e f g h i j k l m n o "Orphanet: Toxic epidermal necrolysis". Orphanet. November 2008. Archived from the original on 27 April 2017. Retrieved 26 April 2017.
  4. ^ a b c d "Stevens-Johnson syndrome". GARD. Archived from the original on 28 August 2016. Retrieved 26 August 2016.
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    PMID 22818644
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  13. ^ a b c Garra, GP (2007). "Toxic Epidermal Necrolysis Archived 2007-12-27 at the Wayback Machine". Emedicine.com. Retrieved on December 13, 2007.
  14. S2CID 45667604
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