toxic epidermal necrolysis

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.{{cite journal|last1=Jordan|first1=MH|last2=Lewis|first2=MS|last3=Jeng|first3=JG|last4=Rees|first4=JM|title=Treatment of toxic epidermal necrolysis by burn units: another market or another threat?|journal=The Journal of Burn Care & Rehabilitation|date=1991|volume=12|issue=6|pages=579–81|pmid=1779014|doi=10.1097/00004630-199111000-00015}}

Initial skin findings include red-purple, dusky, flat spots known as macules that start on the trunk and spread out from there. These skin lesions then transform into large blisters. The affected skin can then become necrotic or sag from the body and peel off in great swaths.

File:Necrolysis epidermalis toxica 02.JPG|Toxic epidermal necrolysis on legs

File:Early stage blisters on the back TENS patient.jpg|alt=TENS Blisters on day 4|The emerging blisters on day 4 of an instance of TENs

File:TENS patient on day 10.jpg|alt=TENS patient back|The back of a TENs patient on day 10, at the peak of the condition

Nearly all people with TEN have oral, eye and genital involvement as well. Painful crusts and erosions may develop on any mucosal surface.{{cite journal|last1=Roujeau|first1=JC|last2=Stern|first2=RS|title=Severe adverse cutaneous reactions to drugs.|journal=The New England Journal of Medicine|date=10 November 1994|volume=331|issue=19|pages=1272–85|pmid=7794310|doi=10.1056/nejm199411103311906}} The mouth becomes blistered and eroded, making eating difficult and sometimes necessitating feeding through a 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.{{cite journal|last1=Morales|first1=ME|last2=Purdue|first2=GF|last3=Verity|first3=SM|last4=Arnoldo|first4=BD|last5=Blomquist|first5=PH|title=Ophthalmic Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Relation to SCORTEN.|journal=American Journal of Ophthalmology|date=October 2010|volume=150|issue=4|pages=505–510.e1|pmid=20619392|doi=10.1016/j.ajo.2010.04.026}}

Those who survive the acute phase of TEN often develop long-term complications affecting the skin and eyes. Skin manifestations can include scarring, eruptive melanocytic nevi, vulvovaginal stenosis, and dyspareunia. The epithelium of the trachea, bronchi, or gastrointestinal tract may be involved in SJS and TEN. Ocular symptoms are the most common complication in TEN, experienced by 20–79% of those with TEN, even by those who do not experience immediate ocular manifestations. These can include dry eyes, photophobia, symblepharon, corneal scarring or xerosis, subconjunctival fibrosis, trichiasis, decreased visual acuity, and blindness.

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

The drugs most often implicated in TEN are:

• antibiotics
• sulfonamides (sulfamethoxazole, sulfadiazine, sulfapyridine)
• beta-lactams (cephalosporins, penicillins, carbapenems)
• nonsteroidal anti-inflammatory drugs
• allopurinol
• antimetabolites (methotrexate)
• antiretroviral drugs (nevirapine)
• corticosteroids
• anxiolytics (chlormezanone)
• anticonvulsants (phenobarbital, phenytoin, carbamazepine, lamotrigine, and valproic acid).Garra, GP (2007). "[http://www.emedicine.com/EMERG/topic599.htm Toxic Epidermal Necrolysis] {{webarchive|url=https://web.archive.org/web/20071227222045/http://www.emedicine.com/EMERG/topic599.htm |date=2007-12-27 }}". Emedicine.com. Retrieved on December 13, 2007.{{Cite journal|last1=Maverakis|first1=Emanual|last2=Wang|first2=Elizabeth A.|last3=Shinkai|first3=Kanade|last4=Mahasirimongkol|first4=Surakameth|last5=Margolis|first5=David J.|last6=Avigan|first6=Mark|last7=Chung|first7=Wen-Hung|last8=Goldman|first8=Jennifer|last9=Grenade|first9=Lois La|date=2017-06-01|title=Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Standard Reporting and Evaluation Guidelines: Results of a National Institutes of Health Working Group|journal=JAMA Dermatology|volume=153|issue=6|pages=587–592|doi=10.1001/jamadermatol.2017.0160|pmid=28296986|s2cid=205110875|issn=2168-6068|url=https://www.zora.uzh.ch/id/eprint/144140/1/LF_2017_Stevens-Johnson_Syndrome_and_Toxic_Necrolysis_Standard_Reporting_and_Evaluation_Guidlines_-_Results_of_a_National_Institutes_of_Health_Working_Group.pdf|access-date=2019-12-12|archive-date=2019-12-03|archive-url=https://web.archive.org/web/20191203081548/https://www.zora.uzh.ch/id/eprint/144140/1/LF_2017_Stevens-Johnson_Syndrome_and_Toxic_Necrolysis_Standard_Reporting_and_Evaluation_Guidlines_-_Results_of_a_National_Institutes_of_Health_Working_Group.pdf|url-status=live}}

TEN has also been reported to result from infection with Mycoplasma pneumoniae or dengue virus. Contrast agents used in imaging studies as well as transplantation of bone marrow or organs have also been linked to TEN development.

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.

Certain genetic factors are associated with increased risk of TEN. For example, certain HLA-types such as, HLA-B*1502,{{cite journal|last1=Hung|first1=SI|last2=Chung|first2=WH|last3=Jee|first3=SH|last4=Chen|first4=WC|last5=Chang|first5=YT|last6=Lee|first6=WR|last7=Hu|first7=SL|last8=Wu|first8=MT|last9=Chen|first9=GS|last10=Wong|first10=TW|last11=Hsiao|first11=PF|last12=Chen|first12=WH|last13=Shih|first13=HY|last14=Fang|first14=WH|last15=Wei|first15=CY|last16=Lou|first16=YH|last17=Huang|first17=YL|last18=Lin|first18=JJ|last19=Chen|first19=YT|title=Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.|journal=Pharmacogenetics and Genomics|date=April 2006|volume=16|issue=4|pages=297–306|pmid=16538176|doi=10.1097/01.fpc.0000199500.46842.4a|s2cid=45667604}} HLA-A*3101,{{cite journal|last1=McCormack|first1=M|last2=Alfirevic|first2=A|last3=Bourgeois|first3=S|last4=Farrell|first4=JJ|last5=Kasperavičiūtė|first5=D|last6=Carrington|first6=M|last7=Sills|first7=GJ|last8=Marson|first8=T|last9=Jia|first9=X|last10=de Bakker|first10=PI|last11=Chinthapalli|first11=K|last12=Molokhia|first12=M|last13=Johnson|first13=MR|last14=O'Connor|first14=GD|last15=Chaila|first15=E|last16=Alhusaini|first16=S|last17=Shianna|first17=KV|last18=Radtke|first18=RA|last19=Heinzen|first19=EL|last20=Walley|first20=N|last21=Pandolfo|first21=M|last22=Pichler|first22=W|last23=Park|first23=BK|last24=Depondt|first24=C|last25=Sisodiya|first25=SM|last26=Goldstein|first26=DB|last27=Deloukas|first27=P|last28=Delanty|first28=N|last29=Cavalleri|first29=GL|last30=Pirmohamed|first30=M|title=HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.|journal=The New England Journal of Medicine|date=24 March 2011|volume=364|issue=12|pages=1134–43|pmid=21428769|doi=10.1056/nejmoa1013297|pmc=3113609}} HLA-B*5801,{{cite journal|last1=Tohkin|first1=M|last2=Kaniwa|first2=N|last3=Saito|first3=Y|last4=Sugiyama|first4=E|last5=Kurose|first5=K|last6=Nishikawa|first6=J|last7=Hasegawa|first7=R|last8=Aihara|first8=M|last9=Matsunaga|first9=K|last10=Abe|first10=M|last11=Furuya|first11=H|last12=Takahashi|first12=Y|last13=Ikeda|first13=H|last14=Muramatsu|first14=M|last15=Ueta|first15=M|last16=Sotozono|first16=C|last17=Kinoshita|first17=S|last18=Ikezawa|first18=Z|last19=Japan Pharmacogenomics Data Science|first19=Consortium|title=A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients.|journal=The Pharmacogenomics Journal|date=February 2013|volume=13|issue=1|pages=60–9|pmid=21912425|doi=10.1038/tpj.2011.41|doi-access=|s2cid=42286060}} and HLA‐B*57:01{{cite journal |last1=Alfirevic |first1=Ana |last2=Pirmohamed |first2=Munir |last3=Marinovic |first3=Branka |last4=Harcourt-Smith |first4=Linda |last5=Jorgensen |first5=Andrea L |last6=Cooper |first6=Tess E |title=Genetic testing for prevention of severe drug-induced skin rash |journal=Cochrane Database of Systematic Reviews |volume=2019 |pages=CD010891 |date=17 July 2019 |issue=7 |doi=10.1002/14651858.CD010891.pub2|pmid=31314143 |pmc=6636675 }} have been seen to be linked with TEN development when exposed to specific drugs.

The immune system's role in the precise pathogenesis of TEN remains unclear. It appears that a certain type of immune cell (cytotoxic CD8+ T cell) is primarily responsible for keratinocyte death and subsequent skin detachment. 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.

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.

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.

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.

Confluent epidermal necrosis - low mag.jpg|Confluent Epidermal Necrosis, low mag

Confluent epidermal necrosis - very high mag.jpg|Confluent Epidermal Necrosis, high mag

• Staphylococcal scalded skin syndrome
• Drug-induced linear immunoglobulin A dermatosis
• Acute graft versus host disease
• Acute generalized exanthematous pustulosis
• Erythroderma
• Drug reaction with eosinophilia and systemic symptoms aka DRESS
• A generalized morbilliform eruption{{cite journal|last1=Schwartz|first1=RA|last2=McDonough|first2=PH|last3=Lee|first3=BW|title=Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment.|journal=Journal of the American Academy of Dermatology|date=Aug 2013|volume=69|issue=2|pages=187.e1–16; quiz 203–4|pmid=23866879|doi=10.1016/j.jaad.2013.05.002}}

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.

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.{{cite journal|last1=Zajicek|first1=R|last2=Pintar|first2=D|last3=Broz|first3=L|last4=Suca|first4=H|last5=Königova|first5=R|title=Toxic epidermal necrolysis and Stevens-Johnson syndrome at the Prague Burn Centre 1998-2008.|journal=Journal of the European Academy of Dermatology and Venereology|date=May 2012|volume=26|issue=5|pages=639–43|pmid=21668825|doi=10.1111/j.1468-3083.2011.04143.x|s2cid=25253929}} Unfortunately, research studies reveal conflicting support for use of IVIG in treatment of TEN.{{cite journal |vauthors=Rajaratnam R, Mann C, Balasubramaniam P, etal |title=Toxic epidermal necrolysis: retrospective analysis of 21 consecutive cases managed at a tertiary centre |journal=Clin. Exp. Dermatol. |volume=35 |issue=8 |pages=853–62 |date=December 2010 |pmid=20456393 |doi=10.1111/j.1365-2230.2010.03826.x |s2cid=1477097 }} 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.

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. A meta-analysis from 2002 concluded that there is no reliable evidence for the treatment of TEN.{{Cite journal|last1=Majumdar|first1=Samit|last2=Mockenhaupt|first2=Maja|last3=Roujeau|first3=Jean-Claude|last4=Townshend|first4=Askari P|date=2002-10-21|title=Interventions for toxic epidermal necrolysis|url=http://www.cochrane.org/CD001435/SKIN_interventions-for-toxic-epidermal-necrolysis|journal=Cochrane Database of Systematic Reviews|volume=2015 |issue=4|pages=CD001435|language=en|doi=10.1002/14651858.CD001435|pmid=12519556|pmc=8958873 |issn=1465-1858|access-date=2018-06-25|archive-date=2018-06-25|archive-url=https://web.archive.org/web/20180625075528/http://www.cochrane.org/CD001435/SKIN_interventions-for-toxic-epidermal-necrolysis|url-status=live}} Thalidomide did not show any benefit and was associated with increased mortality compared with placebo.

The mortality for toxic epidermal necrolysis is 25–30%. People with SJS or TEN caused by a medication have a better prognosis the earlier the causative medication is withdrawn. Loss of the skin leaves patients vulnerable to infections from fungi and bacteria, and can result in sepsis, the leading cause of death in the disease. Death is caused either by infection or by 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.{{cite journal |author=Quinn AM |title=Uncovering histological criteria with prognostic significance in toxic epidermal necrolysis |journal=Arch Dermatol |volume=141 |issue=6 |pages=683–7 |year=2005 |pmid=15967913 |doi=10.1001/archderm.141.6.683 |last2=Brown |first2=K |last3=Bonish |first3=BK |last4=Curry |first4=J |last5=Gordon |first5=KB |last6=Sinacore |first6=J |last7=Gamelli |first7=R |last8=Nickoloff |first8=BJ|display-authors=etal|doi-access= }}

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.{{cite journal|last=Schwartz|first=RA|author2=McDonough, PH |author3=Lee, BW |title=Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment.|journal=Journal of the American Academy of Dermatology|date=August 2013|volume=69|issue=2|pages=187.e1–16; quiz 203–4|pmid=23866879|doi=10.1016/j.jaad.2013.05.002}}

One point is given for each of the following factors:{{cite journal|last=DeMers|first=G|author2=Meurer, WJ |author3=Shih, R |author4=Rosenbaum, S |author5= Vilke, GM |title=Tissue plasminogen activator and stroke: review of the literature for the clinician.|journal=The Journal of Emergency Medicine|date=December 2012|volume=43|issue=6|pages=1149–54|pmid=22818644|doi=10.1016/j.jemermed.2012.05.005}}

• 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

• 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.

{{Reflist}}

• {{MerckHome|18|203|e}}
• [https://web.archive.org/web/20060813085729/http://www.dermnetnz.org/reactions/toxic-epidermal-necrolysis.html DermNetNZ]

{{Urticaria and erythema}}

{{Medical resources

| DiseasesDB = 4450

| ICD10 = {{ICD10|L|51|2|l|50}}

| ICD9 = {{ICD9|695.15}}

| ICDO =

| OMIM = 608579

| MedlinePlus =

| eMedicineSubj = emerg

| eMedicineTopic = 599

| eMedicine_mult = {{eMedicine2|med|2291}} {{eMedicine2|derm|405}}

| MeshID = D004816

}}

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Category:Drug eruptions

Category:Medical emergencies

Category:Wikipedia medicine articles ready to translate

Category:Wikipedia emergency medicine articles ready to translate