Toxic epidermal necrolysis (TEN) is a type of severe
skin reaction
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sy ...
.
Together with
Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe.
[ Early symptoms include fever and flu-like symptoms.][ A few days later the skin begins to blister and peel forming painful raw areas.][ Mucous membranes, such as the mouth, are also typically involved.][ Complications include ]dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
, sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
, pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
, and multiple organ failure.[
The most common cause is certain medications such as ]lamotrigine
Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut sy ...
, carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...
, allopurinol, sulfonamide antibiotics, and nevirapine.[ Other causes can include infections such as '' Mycoplasma pneumoniae'' and ]cytomegalovirus
''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betah ...
or the cause may remain unknown.[ Risk factors include ]HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
and systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
.[ Diagnosis is based on a skin biopsy and involvement of more than 30% of the skin.][ TEN is a type of ]severe cutaneous adverse reactions
Severity or Severely may refer to:
* ''Severity'' (video game), a canceled video game
* "Severely" (song), by South Korean band F.T. Island
See also
*
*
{{disambig ...
(SCARs), together with SJS, a SJS/TEN, and drug reaction with eosinophilia and systemic symptoms. It is called SJS when less than 10% of the skin is involved and an intermediate form with 10 to 30% involvement.[ ]Erythema multiforme
Erythema multiforme (EM) is a skin condition that appears with red patches evolving into target lesions, typically on both hands.
It is a type of erythema possibly mediated by deposition of immune complexes (mostly IgM-bound complexes) in the ...
(EM) is generally considered a separate condition.
Treatment typically takes place in hospital
A hospital is a health care institution providing patient treatment with specialized health science and auxiliary healthcare staff and medical equipment. The best-known type of hospital is the general hospital, which typically has an emergen ...
such as in a burn unit or intensive care unit
220px, Intensive care unit
An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensi ...
. Efforts include stopping the cause, pain medication
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). I ...
, and antihistamines.[ ]Antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...
, intravenous immunoglobulins
Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin or NHIG) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory dem ...
, and corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
may also be used.[ Treatments do not typically change the course of the underlying disease.][ Together with SJS it affects 1 to 2 persons per million per year.][ It is more common in females than males.][ Typical onset is over the age of 40.] Skin usually regrows over two to three weeks; however, recovery can take months and most are left with chronic problems.
Signs and symptoms
Prodrome
TEN ultimately results in extensive skin involvement with redness, necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...
, and detachment of the top (epidermal) layer of the skin and mucosa. Before these severe findings develop, people often have a flu-like prodrome
In medicine, a prodrome is an early sign or symptom (or set of signs and symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. It is derived from the Greek word ''prodromos'', meani ...
, with a cough, runny nose, fever, decreased appetite
Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
and malaise
As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century.
The term is often used ...
. 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.
Skin findings
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
]
Mucosal findings
Nearly all people with TEN have oral, eye and genital involvement as well. Painful crusts and erosions may develop on any mucosal surface. The mouth becomes blistered and eroded, making eating difficult and sometimes necessitating feeding through a nasogastric tube
Nasogastric intubation is a medical process involving the insertion of a plastic tube (nasogastric tube or NG tube) through the nose, down the oesophagus, and down into the stomach. Orogastric intubation is a similar process involving the inserti ...
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
Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. Th ...
.
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 melanocytic nevi, vulvovaginal stenosis, and dyspareunia
Dyspareunia ( ) is painful sexual intercourse due to medical or psychological causes. The term ''dyspareunia'' covers both female dyspareunia and male dyspareunia, but many discussions that use the term without further specification concern the ...
. 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
Dry eye syndrome (DES), also known as keratoconjunctivitis sicca (KCS), is the condition of having dry eyes. Other associated symptoms include irritation, redness, discharge, and easily fatigued eyes. Blurred vision may also occur. Symptoms rang ...
, photophobia, symblepharon
A symblepharon is a partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball. It results either from disease (conjunctival sequelae of trachoma) or trauma. Cicatricial pemphigoid and, in seve ...
, corneal scarring or xerosis, subconjunctival fibrosis, trichiasis, decreased visual acuity, and blindness.
Cause
Drug reactions have been reported to cause 80–95% of TEN cases.[
The drugs most often implicated in TEN are:
* antibiotics
** ]sulfonamides
In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
( sulfamethoxazole, sulfadiazine, sulfapyridine)
** beta-lactams (cephalosporin
The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''.
Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
s, penicillin
Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
s, carbapenem
Carbapenems are a class of very effective antibiotic agents most commonly used for the treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. S ...
s)
* nonsteroidal anti-inflammatory drugs
* allopurinol
* antimetabolites
An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates ...
(methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
)
* antiretroviral drugs (nevirapine)
* corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
* anxiolytic
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...
s ( chlormezanone)
* anticonvulsant
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...
s (phenobarbital
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
, phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
, carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...
, lamotrigine
Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut sy ...
, and valproic acid).[Garra, GP (2007).]
Toxic Epidermal Necrolysis
". Emedicine.com. Retrieved on December 13, 2007.
TEN has also been reported to result from infection with '' Mycoplasma pneumoniae'' or dengue virus
''Dengue virus'' (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family '' Flaviviridae''; genus '' Flavivirus''. Four serotypes of the virus have been found, a reported fifth has yet to ...
. Contrast agents used in imaging studies as well as transplantation of bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
or organs have also been linked to TEN development.[
]
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.[
]
Genetics
Certain genetic factors are associated with increased risk of TEN. For example, certain HLA-types such as, HLA-B*1502, HLA-A*3101, HLA-B*5801, and HLA‐B*57:01 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 ( cytotoxic CD8+ T cell) is primarily responsible for keratinocyte death and subsequent skin detachment. Keratinocytes
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
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.[
]
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.[
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.][
]
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.[
Confluent epidermal necrosis - low mag.jpg, Confluent Epidermal Necrosis, low mag
Confluent epidermal necrosis - very high mag.jpg, Confluent Epidermal Necrosis, high mag
]
Differential diagnosis
* Staphylococcal scalded skin syndrome
* Drug-induced linear immunoglobulin A dermatosis
* Acute graft versus host disease
* Acute generalized exanthematous pustulosis
Acute generalized exanthematous pustulosis (AGEP) (also known as pustular drug eruption and toxic pustuloderma) is a rare skin reaction that in 90% of cases is related to medication administration.
AGEP is characterized by sudden skin eruptions th ...
* Erythroderma
* Drug reaction with eosinophilia and systemic symptoms aka DRESS
* A generalized morbilliform eruption
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 unit
220px, Intensive care unit
An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensi ...
s, supportive management, and nutritional support.[
Current literature does not convincingly support use of any adjuvant systemic therapy. Initial interest in ]Intravenous immunoglobulin
Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin or NHIG) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory ...
(IVIG) came from research showing that IVIG could inhibit Fas-FasL mediated keratinocyte apoptosis in vitro. Unfortunately, research studies reveal conflicting support for use of IVIG in treatment of TEN. 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
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
, ciclosporin, cyclophosphamide
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
, plasmapheresis, pentoxifylline
Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease. It is generic and sold under many brand names worldwide.Drugs.codrugs.com international listings ...
, acetylcysteine
Acetylcysteine, also known as ''N''-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been us ...
, ulinastatin
Ulinastatin, as an urinary trypsin inhibitor (UTI), is a glycoprotein that is isolated from healthy human urine or synthetically produced and has molecular weight of 25 - 40kDa. Highly purified ulinastatin has been clinically used for the treatme ...
, infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
, and granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.
Functiona ...
s (if TEN associated-leukopenia
Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of ...
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.] Thalidomide
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
did not show any benefit and was associated with increased mortality compared with placebo.
Prognosis
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
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...
and bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
, and can result in sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
, the leading cause of death in the disease.[ Death is caused either by ]infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
or by respiratory distress
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...
which is either due to pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
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.
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.
One point is given for each of the following factors:
* 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.
References
External links
*
DermNetNZ
{{Urticaria and erythema
Drug eruptions
Medical emergencies
Wikipedia medicine articles ready to translate
Wikipedia emergency medicine articles ready to translate