Extensive peeling of the epidermis & mucous membrane is a hallmark of toxic epidermal necrolysis (TEN), a potentially fatal illness that can cause sepsis & death. Alan Lyell first referred to it as “an eruption mimicking scorching of the skin” in 1956. TEN typically results from an immunological response to particular medications.
Tumors, infection, & immunization have all been listed as probable reasons, though. The disease process that characterizes Steven-Johnson Syndrome (SJS) is the same as that seen in drug-induced epidermolysis. The degree of skin separation is the fundamental distinction. SJS often affects less than 10% of the whole-body surface area, whereas TEN typically involves over 30%.
Epidemiology
In the US, 1.9 per million adults are thought to get TEN each year, whereas 9.3 per million individuals are thought to develop SJS. There are a lot of reports from various places. According to a 1996 German study, there are roughly 1.9 incidences of SJS & TEN per million people per year. Between 1995 – 2013, the reported rate for combined SJS & TEN cases in the UK was as high as 5.76 cases per million people per year.
While TEN affects roughly one sufferer per million individuals annually in Japan. According to the majority of studies, Asian & black patients are more vulnerable than the white population. According to some research, the risk is twice as high for Asian & Black people. With a ratio of 1.5 females to every male, there is a definite preference for women.
Most TEN patients are in their fifth to seventh decade of life. However, it can impact people of any age. In general, drug use is the primary cause of instances in adults, whereas infections are the primary cause in youngsters. Numerous recent research have emphasised the link between various HLA alleles and the emergence of TEN, particularly in the Southeast Asian population.
Anatomy
Pathophysiology
TEN was once thought to be connected to granulysin- or Fas-Fas ligand-mediated apoptosis. Reactive oxygen species (ROS) have been suggested in more recent investigations as the initial cause of keratinocyte destruction and as occurring before the activation of the apoptotic mechanisms listed above. Fas is a membrane-bound protein that triggers a cascade of intracellular actions that lead to programmed cell death. Fas ligand (FasL), which is often produced by natural killer (NK) & cytotoxic T (CTL) cells, binds to Fas on target cells and causes apoptosis.
These cells are not the source of FasL, as evidenced by the fact that there are few of them in skin biopsies performed from TEN patients. In a 1998 study by Virad et al., it was discovered that FasL was highly localised on keratinocytes. This implies that keratinocytes could be the cause of their own demise. A pro-apoptotic protein called granulysin was found in TEN blisters as well. It is one of a large number of cytotoxic chemicals that CTL & NK cells produce, and which cause cell-mediated cytotoxic.
One of the TEN hypotheses that has been put forth is oxidative stress. In keratinocytes, glutathione S-transferase-p (GST-p) is an indicator of oxidative stress. In contrast to other cutaneous drug interactions, a higher concentration of this marker has been found in TEN patients. The offending medicine may obstruct detoxification processes, causing reactive oxygen molecules (ROS) to build up and eventually cause programmed death of cells.
Etiology
Medication side effects, infections, vaccinations, and even idiopathic causes can cause TEN. The most frequent reason is by far an adverse medication reaction. Several pharmaceuticals, including antiepileptics (lamotrigine, barbiturate, valproate, phenytoin, and carbamazepine), non-steroidal anti-inflammatory drugs (NSAID), particularly piroxicam and oxybutazone, antiviral treatments (abacavir and oseltamivir), & allopurinol, have been related to TEN.
Lamotrigine, sulfonamide, phenytoin, carbamazepine, phenobarbital, nevirapine, sulfasalazine, oxicam-NSAIDs, and allopurinol are medicines having a high risk of TEN, based on the 2008 Euro-SCAR research. Within the first four weeks of the start of the treatment, the majority of instances manifest.
Other probable causes include vaccination, particularly the meningococcal vaccine, infections such mycoplasma pneumoniae, human herpesvirus 7 and hepatitis A, cancers like hepatocellular carcinomas & lung carcinomas, and hepatitis A & human herpesvirus 7. As a result of the viral infection or the drugs taken during the period of treatment, TEN has more recently been documented in COVID-19 individuals.
Genetics
Prognostic Factors
TEN cases had a documented mortality rate of 25 – 30% compared to SJS cases’ 1 to 5%. The severity of cutaneous affection affects the outcome of TEN cases.
The death rate increases with afflicted body surface area. The leading factor in death is infection. Pulmonary embolism, adult respiratory distress syndrome, kidney & heart failure, & GI bleeding are additional potentially fatal consequences.
Clinical History
Clinical History
Patients with toxic epidermal necrolysis (TEN) may speak of the following influenza-like symptoms as the prodrome:
Anorexia
Headache
Rhinitis
Myalgia
Arthralgia
Cough
Fever
Rash
Malaise
Conjunctivitis (32 percent), pruritus (28 percent), and pharyngitis (25 percent) are other prodromal symptoms. The prodrome might last anywhere from one day to three weeks on average. An erythematous macula rash with purpuric centres that is vaguely defined marks the beginning of the cutaneous eruption. The rash develops into flaccid blisters & sheet-like epidermal peeling over the course of many hours to days. 90% of the time, mucous membrane erosions occur prior to skin lesions by 1-3 days.
The oropharynx, following by the genitalia & eyes, is the mucosal membrane that is most frequently impacted. A sore and burning experience is the typical first sign of oral cavity involvement. The discomfort caused by the oropharyngeal lesions may limit intake. Acute conjunctivitis, corneal erosions, & ulcers are only a few examples of eye symptoms. Urination may be painful as a result of genital involvement. Diverse gastric involvement, including colonic, esophageal, & ileal mucosa involvement, is highly uncommon. There have been recommended more than 220 different medicines.
The following list includes the most often mentioned agents:
Less than 5% of patients say they have never used any medications.
Physical Examination
Physical examination
In toxic epidermal necrolysis, tachycardia, hypotension brought on by hypovolemia, and hyperpyrexia are all possible vital signs.
Skin examination
Skin lesions start as distinct, morbilliform macules, erythematous that are first unpleasant or blistering. Before spreading throughout the entire body, they start symmetrically on the face & thorax. Large, flaccid blisters form as a result of the skin lesions coalescing and filling with fluid. The epidermis sheds in sheets, exposing the dermis, which is often wet and bare. Epidermal necrolysis is preceded by conjunctivitis, denudation, and erosions of various mucous membranes.
When the epidermis easily separates from its underlying surface in response to light lateral pressure applied to it, this is known as a positive Nikolsky sign. The typical course begins with a severe erythema, moves quickly to epidermolysis, and then ceases after two to three days. Mucosal lesions require lengthier healing times than skin lesions, which commonly takes 1-3 weeks. Necrolysis rarely returns in places that have started to recover. Edema and erythema are brought on by oral mucosa involvement, which is then followed by blistering.
Blisters that rupture might develop superficial aphthous-like ulcers or widespread hemorrhagic erosions with pseudomembranes that are greyish white. Lip hemorrhagic crusting is a frequent finding. Ocular involvement can cause minor inflammation, purulent exudates, conjunctival erosion, or the creation of pseudomembranes and ranges in severity. Bronchial hypersecretion, bacterial pneumonia, interstitial infiltrates, hypoxemia, pulmonary edoema, & bronchiolitis obliterans can all be brought on by engagement of the respiratory epithelium.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential diagnosis
Toxic epidermal necrolysis (TEN) & Stevens-Johnson syndrome (SJS) belong to the same illness spectrum. The severity of the skin affliction is the only distinction. SJS is present when epidermal detachment accounts for less than 10 percent of the body’s total surface area. While this is deemed TEN if the damaged body surface area exceeds 30%. When between 10% and 29% of the body surface area is damaged, there is overlap among the two diseases. EMM (Erythema multiform major) is the primary differential diagnosis. It is characterised by the symmetrical acral distribution of target lesions with or without blister development & primarily affects less than 10% of total body surface area.
SJS & TEN, in contrast, are characterised primarily by cutaneous blisters that develop atop erythematous nodules in a centralized distribution (trunk and face). In addition, 90% of SJS & TEN cases include 2 or even more mucosal areas.
Other possible differential diagnoses are:
Children with Staphylococcal scalded skin syndrome: (No history of drug use, staphylococcal infection, and it typically spares mucous membranes)
Exfoliative erythroderma (most of the time merely affects the skin, spares the mucous membranes, and causes no pain)
Paraneoplastic pemphigus
Toxic shock syndrome
various drug rashes
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Supportive care is the mainstay of TEN treatment until the damaged skin has been re-epithelialized. Fluid resuscitation, wound treatment, pain relief and dietary assistance are examples of supportive interventions. Two key aspects of early management of these individuals in the emergency room should be the cessation of the offending medicine and the prompt referral to a intensive care unit or burn unit with expertise in handling such cases.
These two actions reduce hospital stays and infection rates when administered within the initial 24 hours of blisters development, and they also increase overall survivability. The airway should be monitored often, & supplemental oxygen should be given using a facial mask if necessary. An specialist should perform endotracheal intubation in cases of respiratory crisis. One of the standard burn resuscitation Performas should be used to guide fluid resuscitation using crystalloids (e.g., Parkland formula).
By attaining an appropriate mean arterial blood pressure (ABP>65mm Hg), a central venous pressure between 8 and 12 mmHg, and a urine output of 0.5 to 1 ml/kg/hour, the goal of resuscitation should be to maintain adequate tissue perfusion. The management of pain is crucial for reducing patient misery. It is possible to employ opiates and PCA (patient-controlled analgesia).
Skin erosions should be covered with a non-adhesive sterile covering, and hypothermia should be avoided at all costs, particularly in the prehospital situation. The hypercatabolic nature of TEN makes nutritional supplementation essential for patients. Because enteral feeding reduces the chance of bacterial translocation, it is preferable to parenteral feeding. Nasogastric tubes might be utilised if the oral mucosa is significantly damaged. Carefully assess the amount of energy and dietary support needed (target for 20 to 25 kcal/kg/day).
Wound Care
Prior to re-epithelialization, aseptic wound care is crucial to preventing subsequent infection. Mucosal lesions can take longer to heal than skin lesions, which typically do so in 2 weeks. For the treatment of wounds, there is no set method. There isn’t much solid data to support debridement of the afflicted skin either early, late, or not at all. Debridement of a wound should be performed while under local anaesthetic. Xenograft, allograft, & homograft are examples of biological dressings. Biobrane is an example of a biosynthetic dressing. Silver-impregnated dressing is another possibility. Additionally, effective wound care will lower the need for analgesics.
Infection is widespread and can be fatal. The most frequent infection is staphylococcal, accompanied by pseudomonas infection, which happens after a lengthy hospital stay. Antibiotics for prevention are not advised because the survival chances remain unchanged. To find and treat an early infection, skin lesions should, however, be microbiologically assessed on the day of presentation & every 48 hours. Skin swabs showing signs of infection, a patient’s condition rapidly deteriorating, or a fast drop in temperature are all indications that antibiotic treatment is necessary. Anaerobes, gram-positive and gram-negative organisms, and all of them should be covered with empirical antibiotics.
Pharmacotherapy
Systemic steroids, cyclosporin, plasmapheresis, TNF-alpha (anti-tumor necrosis factor-alpha), & IVIG (intravenous immunoglobulin) have all been tried without success. All of the clinical information that has been published on these drugs is anecdotal and based primarily on observational studies. It is very difficult to conduct high-quality randomized controlled studies to evaluate the effectiveness of these treatment approaches because TEN cases are so uncommon. Steroids administered systemically are frequently used to stop TEN cases from progressing.
However, several research connected steroids with a rise in mortality. Three days of daily plasmapheresis may help to further eliminate the harmful drug, its metabolites, & inflammatory cytokines. However, these findings are not supported by a prospective randomised trial. In afflicted keratinocytes of skin lesions, particularly in skin blisters, TNF-alpha is overexpressed. According to certain research, TNF- alpha inhibitors can cause skin lesions to heal quickly. When administered within the initial 72 hours, IVIG also demonstrated favourable benefits.
Complications
Ocular problems are frequent and occasionally significant. Immediate ophthalmological evaluation is essential, and topical lubricants or steroid drops, or antibiotics are frequently used as treatments. Genitourinary issues are also frequent. To encourage mucosal recovery, topical oestrogen is used.
Menstrual suppression may be useful in extreme situations to reduce the chance of developing vaginal adenosis. Other medical professionals, such as those in urology, otolaryngology, & pulmonary medicine, may be required to provide additional insight based on the clinical picture. All TEN patients should also be evaluated to see if they require psychological treatment after discharge.
Extensive peeling of the epidermis & mucous membrane is a hallmark of toxic epidermal necrolysis (TEN), a potentially fatal illness that can cause sepsis & death. Alan Lyell first referred to it as “an eruption mimicking scorching of the skin” in 1956. TEN typically results from an immunological response to particular medications.
Tumors, infection, & immunization have all been listed as probable reasons, though. The disease process that characterizes Steven-Johnson Syndrome (SJS) is the same as that seen in drug-induced epidermolysis. The degree of skin separation is the fundamental distinction. SJS often affects less than 10% of the whole-body surface area, whereas TEN typically involves over 30%.
In the US, 1.9 per million adults are thought to get TEN each year, whereas 9.3 per million individuals are thought to develop SJS. There are a lot of reports from various places. According to a 1996 German study, there are roughly 1.9 incidences of SJS & TEN per million people per year. Between 1995 – 2013, the reported rate for combined SJS & TEN cases in the UK was as high as 5.76 cases per million people per year.
While TEN affects roughly one sufferer per million individuals annually in Japan. According to the majority of studies, Asian & black patients are more vulnerable than the white population. According to some research, the risk is twice as high for Asian & Black people. With a ratio of 1.5 females to every male, there is a definite preference for women.
Most TEN patients are in their fifth to seventh decade of life. However, it can impact people of any age. In general, drug use is the primary cause of instances in adults, whereas infections are the primary cause in youngsters. Numerous recent research have emphasised the link between various HLA alleles and the emergence of TEN, particularly in the Southeast Asian population.
TEN was once thought to be connected to granulysin- or Fas-Fas ligand-mediated apoptosis. Reactive oxygen species (ROS) have been suggested in more recent investigations as the initial cause of keratinocyte destruction and as occurring before the activation of the apoptotic mechanisms listed above. Fas is a membrane-bound protein that triggers a cascade of intracellular actions that lead to programmed cell death. Fas ligand (FasL), which is often produced by natural killer (NK) & cytotoxic T (CTL) cells, binds to Fas on target cells and causes apoptosis.
These cells are not the source of FasL, as evidenced by the fact that there are few of them in skin biopsies performed from TEN patients. In a 1998 study by Virad et al., it was discovered that FasL was highly localised on keratinocytes. This implies that keratinocytes could be the cause of their own demise. A pro-apoptotic protein called granulysin was found in TEN blisters as well. It is one of a large number of cytotoxic chemicals that CTL & NK cells produce, and which cause cell-mediated cytotoxic.
One of the TEN hypotheses that has been put forth is oxidative stress. In keratinocytes, glutathione S-transferase-p (GST-p) is an indicator of oxidative stress. In contrast to other cutaneous drug interactions, a higher concentration of this marker has been found in TEN patients. The offending medicine may obstruct detoxification processes, causing reactive oxygen molecules (ROS) to build up and eventually cause programmed death of cells.
Medication side effects, infections, vaccinations, and even idiopathic causes can cause TEN. The most frequent reason is by far an adverse medication reaction. Several pharmaceuticals, including antiepileptics (lamotrigine, barbiturate, valproate, phenytoin, and carbamazepine), non-steroidal anti-inflammatory drugs (NSAID), particularly piroxicam and oxybutazone, antiviral treatments (abacavir and oseltamivir), & allopurinol, have been related to TEN.
Lamotrigine, sulfonamide, phenytoin, carbamazepine, phenobarbital, nevirapine, sulfasalazine, oxicam-NSAIDs, and allopurinol are medicines having a high risk of TEN, based on the 2008 Euro-SCAR research. Within the first four weeks of the start of the treatment, the majority of instances manifest.
Other probable causes include vaccination, particularly the meningococcal vaccine, infections such mycoplasma pneumoniae, human herpesvirus 7 and hepatitis A, cancers like hepatocellular carcinomas & lung carcinomas, and hepatitis A & human herpesvirus 7. As a result of the viral infection or the drugs taken during the period of treatment, TEN has more recently been documented in COVID-19 individuals.
TEN cases had a documented mortality rate of 25 – 30% compared to SJS cases’ 1 to 5%. The severity of cutaneous affection affects the outcome of TEN cases.
The death rate increases with afflicted body surface area. The leading factor in death is infection. Pulmonary embolism, adult respiratory distress syndrome, kidney & heart failure, & GI bleeding are additional potentially fatal consequences.
Clinical History
Patients with toxic epidermal necrolysis (TEN) may speak of the following influenza-like symptoms as the prodrome:
Anorexia
Headache
Rhinitis
Myalgia
Arthralgia
Cough
Fever
Rash
Malaise
Conjunctivitis (32 percent), pruritus (28 percent), and pharyngitis (25 percent) are other prodromal symptoms. The prodrome might last anywhere from one day to three weeks on average. An erythematous macula rash with purpuric centres that is vaguely defined marks the beginning of the cutaneous eruption. The rash develops into flaccid blisters & sheet-like epidermal peeling over the course of many hours to days. 90% of the time, mucous membrane erosions occur prior to skin lesions by 1-3 days.
The oropharynx, following by the genitalia & eyes, is the mucosal membrane that is most frequently impacted. A sore and burning experience is the typical first sign of oral cavity involvement. The discomfort caused by the oropharyngeal lesions may limit intake. Acute conjunctivitis, corneal erosions, & ulcers are only a few examples of eye symptoms. Urination may be painful as a result of genital involvement. Diverse gastric involvement, including colonic, esophageal, & ileal mucosa involvement, is highly uncommon. There have been recommended more than 220 different medicines.
The following list includes the most often mentioned agents:
Less than 5% of patients say they have never used any medications.
Physical examination
In toxic epidermal necrolysis, tachycardia, hypotension brought on by hypovolemia, and hyperpyrexia are all possible vital signs.
Skin examination
Skin lesions start as distinct, morbilliform macules, erythematous that are first unpleasant or blistering. Before spreading throughout the entire body, they start symmetrically on the face & thorax. Large, flaccid blisters form as a result of the skin lesions coalescing and filling with fluid. The epidermis sheds in sheets, exposing the dermis, which is often wet and bare. Epidermal necrolysis is preceded by conjunctivitis, denudation, and erosions of various mucous membranes.
When the epidermis easily separates from its underlying surface in response to light lateral pressure applied to it, this is known as a positive Nikolsky sign. The typical course begins with a severe erythema, moves quickly to epidermolysis, and then ceases after two to three days. Mucosal lesions require lengthier healing times than skin lesions, which commonly takes 1-3 weeks. Necrolysis rarely returns in places that have started to recover. Edema and erythema are brought on by oral mucosa involvement, which is then followed by blistering.
Blisters that rupture might develop superficial aphthous-like ulcers or widespread hemorrhagic erosions with pseudomembranes that are greyish white. Lip hemorrhagic crusting is a frequent finding. Ocular involvement can cause minor inflammation, purulent exudates, conjunctival erosion, or the creation of pseudomembranes and ranges in severity. Bronchial hypersecretion, bacterial pneumonia, interstitial infiltrates, hypoxemia, pulmonary edoema, & bronchiolitis obliterans can all be brought on by engagement of the respiratory epithelium.
Differential diagnosis
Toxic epidermal necrolysis (TEN) & Stevens-Johnson syndrome (SJS) belong to the same illness spectrum. The severity of the skin affliction is the only distinction. SJS is present when epidermal detachment accounts for less than 10 percent of the body’s total surface area. While this is deemed TEN if the damaged body surface area exceeds 30%. When between 10% and 29% of the body surface area is damaged, there is overlap among the two diseases. EMM (Erythema multiform major) is the primary differential diagnosis. It is characterised by the symmetrical acral distribution of target lesions with or without blister development & primarily affects less than 10% of total body surface area.
SJS & TEN, in contrast, are characterised primarily by cutaneous blisters that develop atop erythematous nodules in a centralized distribution (trunk and face). In addition, 90% of SJS & TEN cases include 2 or even more mucosal areas.
Other possible differential diagnoses are:
Children with Staphylococcal scalded skin syndrome: (No history of drug use, staphylococcal infection, and it typically spares mucous membranes)
Exfoliative erythroderma (most of the time merely affects the skin, spares the mucous membranes, and causes no pain)
Paraneoplastic pemphigus
Toxic shock syndrome
various drug rashes
Supportive care is the mainstay of TEN treatment until the damaged skin has been re-epithelialized. Fluid resuscitation, wound treatment, pain relief and dietary assistance are examples of supportive interventions. Two key aspects of early management of these individuals in the emergency room should be the cessation of the offending medicine and the prompt referral to a intensive care unit or burn unit with expertise in handling such cases.
These two actions reduce hospital stays and infection rates when administered within the initial 24 hours of blisters development, and they also increase overall survivability. The airway should be monitored often, & supplemental oxygen should be given using a facial mask if necessary. An specialist should perform endotracheal intubation in cases of respiratory crisis. One of the standard burn resuscitation Performas should be used to guide fluid resuscitation using crystalloids (e.g., Parkland formula).
By attaining an appropriate mean arterial blood pressure (ABP>65mm Hg), a central venous pressure between 8 and 12 mmHg, and a urine output of 0.5 to 1 ml/kg/hour, the goal of resuscitation should be to maintain adequate tissue perfusion. The management of pain is crucial for reducing patient misery. It is possible to employ opiates and PCA (patient-controlled analgesia).
Skin erosions should be covered with a non-adhesive sterile covering, and hypothermia should be avoided at all costs, particularly in the prehospital situation. The hypercatabolic nature of TEN makes nutritional supplementation essential for patients. Because enteral feeding reduces the chance of bacterial translocation, it is preferable to parenteral feeding. Nasogastric tubes might be utilised if the oral mucosa is significantly damaged. Carefully assess the amount of energy and dietary support needed (target for 20 to 25 kcal/kg/day).
Wound Care
Prior to re-epithelialization, aseptic wound care is crucial to preventing subsequent infection. Mucosal lesions can take longer to heal than skin lesions, which typically do so in 2 weeks. For the treatment of wounds, there is no set method. There isn’t much solid data to support debridement of the afflicted skin either early, late, or not at all. Debridement of a wound should be performed while under local anaesthetic. Xenograft, allograft, & homograft are examples of biological dressings. Biobrane is an example of a biosynthetic dressing. Silver-impregnated dressing is another possibility. Additionally, effective wound care will lower the need for analgesics.
Infection is widespread and can be fatal. The most frequent infection is staphylococcal, accompanied by pseudomonas infection, which happens after a lengthy hospital stay. Antibiotics for prevention are not advised because the survival chances remain unchanged. To find and treat an early infection, skin lesions should, however, be microbiologically assessed on the day of presentation & every 48 hours. Skin swabs showing signs of infection, a patient’s condition rapidly deteriorating, or a fast drop in temperature are all indications that antibiotic treatment is necessary. Anaerobes, gram-positive and gram-negative organisms, and all of them should be covered with empirical antibiotics.
Pharmacotherapy
Systemic steroids, cyclosporin, plasmapheresis, TNF-alpha (anti-tumor necrosis factor-alpha), & IVIG (intravenous immunoglobulin) have all been tried without success. All of the clinical information that has been published on these drugs is anecdotal and based primarily on observational studies. It is very difficult to conduct high-quality randomized controlled studies to evaluate the effectiveness of these treatment approaches because TEN cases are so uncommon. Steroids administered systemically are frequently used to stop TEN cases from progressing.
However, several research connected steroids with a rise in mortality. Three days of daily plasmapheresis may help to further eliminate the harmful drug, its metabolites, & inflammatory cytokines. However, these findings are not supported by a prospective randomised trial. In afflicted keratinocytes of skin lesions, particularly in skin blisters, TNF-alpha is overexpressed. According to certain research, TNF- alpha inhibitors can cause skin lesions to heal quickly. When administered within the initial 72 hours, IVIG also demonstrated favourable benefits.
Complications
Ocular problems are frequent and occasionally significant. Immediate ophthalmological evaluation is essential, and topical lubricants or steroid drops, or antibiotics are frequently used as treatments. Genitourinary issues are also frequent. To encourage mucosal recovery, topical oestrogen is used.
Menstrual suppression may be useful in extreme situations to reduce the chance of developing vaginal adenosis. Other medical professionals, such as those in urology, otolaryngology, & pulmonary medicine, may be required to provide additional insight based on the clinical picture. All TEN patients should also be evaluated to see if they require psychological treatment after discharge.
Extensive peeling of the epidermis & mucous membrane is a hallmark of toxic epidermal necrolysis (TEN), a potentially fatal illness that can cause sepsis & death. Alan Lyell first referred to it as “an eruption mimicking scorching of the skin” in 1956. TEN typically results from an immunological response to particular medications.
Tumors, infection, & immunization have all been listed as probable reasons, though. The disease process that characterizes Steven-Johnson Syndrome (SJS) is the same as that seen in drug-induced epidermolysis. The degree of skin separation is the fundamental distinction. SJS often affects less than 10% of the whole-body surface area, whereas TEN typically involves over 30%.
In the US, 1.9 per million adults are thought to get TEN each year, whereas 9.3 per million individuals are thought to develop SJS. There are a lot of reports from various places. According to a 1996 German study, there are roughly 1.9 incidences of SJS & TEN per million people per year. Between 1995 – 2013, the reported rate for combined SJS & TEN cases in the UK was as high as 5.76 cases per million people per year.
While TEN affects roughly one sufferer per million individuals annually in Japan. According to the majority of studies, Asian & black patients are more vulnerable than the white population. According to some research, the risk is twice as high for Asian & Black people. With a ratio of 1.5 females to every male, there is a definite preference for women.
Most TEN patients are in their fifth to seventh decade of life. However, it can impact people of any age. In general, drug use is the primary cause of instances in adults, whereas infections are the primary cause in youngsters. Numerous recent research have emphasised the link between various HLA alleles and the emergence of TEN, particularly in the Southeast Asian population.
TEN was once thought to be connected to granulysin- or Fas-Fas ligand-mediated apoptosis. Reactive oxygen species (ROS) have been suggested in more recent investigations as the initial cause of keratinocyte destruction and as occurring before the activation of the apoptotic mechanisms listed above. Fas is a membrane-bound protein that triggers a cascade of intracellular actions that lead to programmed cell death. Fas ligand (FasL), which is often produced by natural killer (NK) & cytotoxic T (CTL) cells, binds to Fas on target cells and causes apoptosis.
These cells are not the source of FasL, as evidenced by the fact that there are few of them in skin biopsies performed from TEN patients. In a 1998 study by Virad et al., it was discovered that FasL was highly localised on keratinocytes. This implies that keratinocytes could be the cause of their own demise. A pro-apoptotic protein called granulysin was found in TEN blisters as well. It is one of a large number of cytotoxic chemicals that CTL & NK cells produce, and which cause cell-mediated cytotoxic.
One of the TEN hypotheses that has been put forth is oxidative stress. In keratinocytes, glutathione S-transferase-p (GST-p) is an indicator of oxidative stress. In contrast to other cutaneous drug interactions, a higher concentration of this marker has been found in TEN patients. The offending medicine may obstruct detoxification processes, causing reactive oxygen molecules (ROS) to build up and eventually cause programmed death of cells.
Medication side effects, infections, vaccinations, and even idiopathic causes can cause TEN. The most frequent reason is by far an adverse medication reaction. Several pharmaceuticals, including antiepileptics (lamotrigine, barbiturate, valproate, phenytoin, and carbamazepine), non-steroidal anti-inflammatory drugs (NSAID), particularly piroxicam and oxybutazone, antiviral treatments (abacavir and oseltamivir), & allopurinol, have been related to TEN.
Lamotrigine, sulfonamide, phenytoin, carbamazepine, phenobarbital, nevirapine, sulfasalazine, oxicam-NSAIDs, and allopurinol are medicines having a high risk of TEN, based on the 2008 Euro-SCAR research. Within the first four weeks of the start of the treatment, the majority of instances manifest.
Other probable causes include vaccination, particularly the meningococcal vaccine, infections such mycoplasma pneumoniae, human herpesvirus 7 and hepatitis A, cancers like hepatocellular carcinomas & lung carcinomas, and hepatitis A & human herpesvirus 7. As a result of the viral infection or the drugs taken during the period of treatment, TEN has more recently been documented in COVID-19 individuals.
TEN cases had a documented mortality rate of 25 – 30% compared to SJS cases’ 1 to 5%. The severity of cutaneous affection affects the outcome of TEN cases.
The death rate increases with afflicted body surface area. The leading factor in death is infection. Pulmonary embolism, adult respiratory distress syndrome, kidney & heart failure, & GI bleeding are additional potentially fatal consequences.
Clinical History
Patients with toxic epidermal necrolysis (TEN) may speak of the following influenza-like symptoms as the prodrome:
Anorexia
Headache
Rhinitis
Myalgia
Arthralgia
Cough
Fever
Rash
Malaise
Conjunctivitis (32 percent), pruritus (28 percent), and pharyngitis (25 percent) are other prodromal symptoms. The prodrome might last anywhere from one day to three weeks on average. An erythematous macula rash with purpuric centres that is vaguely defined marks the beginning of the cutaneous eruption. The rash develops into flaccid blisters & sheet-like epidermal peeling over the course of many hours to days. 90% of the time, mucous membrane erosions occur prior to skin lesions by 1-3 days.
The oropharynx, following by the genitalia & eyes, is the mucosal membrane that is most frequently impacted. A sore and burning experience is the typical first sign of oral cavity involvement. The discomfort caused by the oropharyngeal lesions may limit intake. Acute conjunctivitis, corneal erosions, & ulcers are only a few examples of eye symptoms. Urination may be painful as a result of genital involvement. Diverse gastric involvement, including colonic, esophageal, & ileal mucosa involvement, is highly uncommon. There have been recommended more than 220 different medicines.
The following list includes the most often mentioned agents:
Less than 5% of patients say they have never used any medications.
Physical examination
In toxic epidermal necrolysis, tachycardia, hypotension brought on by hypovolemia, and hyperpyrexia are all possible vital signs.
Skin examination
Skin lesions start as distinct, morbilliform macules, erythematous that are first unpleasant or blistering. Before spreading throughout the entire body, they start symmetrically on the face & thorax. Large, flaccid blisters form as a result of the skin lesions coalescing and filling with fluid. The epidermis sheds in sheets, exposing the dermis, which is often wet and bare. Epidermal necrolysis is preceded by conjunctivitis, denudation, and erosions of various mucous membranes.
When the epidermis easily separates from its underlying surface in response to light lateral pressure applied to it, this is known as a positive Nikolsky sign. The typical course begins with a severe erythema, moves quickly to epidermolysis, and then ceases after two to three days. Mucosal lesions require lengthier healing times than skin lesions, which commonly takes 1-3 weeks. Necrolysis rarely returns in places that have started to recover. Edema and erythema are brought on by oral mucosa involvement, which is then followed by blistering.
Blisters that rupture might develop superficial aphthous-like ulcers or widespread hemorrhagic erosions with pseudomembranes that are greyish white. Lip hemorrhagic crusting is a frequent finding. Ocular involvement can cause minor inflammation, purulent exudates, conjunctival erosion, or the creation of pseudomembranes and ranges in severity. Bronchial hypersecretion, bacterial pneumonia, interstitial infiltrates, hypoxemia, pulmonary edoema, & bronchiolitis obliterans can all be brought on by engagement of the respiratory epithelium.
Differential diagnosis
Toxic epidermal necrolysis (TEN) & Stevens-Johnson syndrome (SJS) belong to the same illness spectrum. The severity of the skin affliction is the only distinction. SJS is present when epidermal detachment accounts for less than 10 percent of the body’s total surface area. While this is deemed TEN if the damaged body surface area exceeds 30%. When between 10% and 29% of the body surface area is damaged, there is overlap among the two diseases. EMM (Erythema multiform major) is the primary differential diagnosis. It is characterised by the symmetrical acral distribution of target lesions with or without blister development & primarily affects less than 10% of total body surface area.
SJS & TEN, in contrast, are characterised primarily by cutaneous blisters that develop atop erythematous nodules in a centralized distribution (trunk and face). In addition, 90% of SJS & TEN cases include 2 or even more mucosal areas.
Other possible differential diagnoses are:
Children with Staphylococcal scalded skin syndrome: (No history of drug use, staphylococcal infection, and it typically spares mucous membranes)
Exfoliative erythroderma (most of the time merely affects the skin, spares the mucous membranes, and causes no pain)
Paraneoplastic pemphigus
Toxic shock syndrome
various drug rashes
Supportive care is the mainstay of TEN treatment until the damaged skin has been re-epithelialized. Fluid resuscitation, wound treatment, pain relief and dietary assistance are examples of supportive interventions. Two key aspects of early management of these individuals in the emergency room should be the cessation of the offending medicine and the prompt referral to a intensive care unit or burn unit with expertise in handling such cases.
These two actions reduce hospital stays and infection rates when administered within the initial 24 hours of blisters development, and they also increase overall survivability. The airway should be monitored often, & supplemental oxygen should be given using a facial mask if necessary. An specialist should perform endotracheal intubation in cases of respiratory crisis. One of the standard burn resuscitation Performas should be used to guide fluid resuscitation using crystalloids (e.g., Parkland formula).
By attaining an appropriate mean arterial blood pressure (ABP>65mm Hg), a central venous pressure between 8 and 12 mmHg, and a urine output of 0.5 to 1 ml/kg/hour, the goal of resuscitation should be to maintain adequate tissue perfusion. The management of pain is crucial for reducing patient misery. It is possible to employ opiates and PCA (patient-controlled analgesia).
Skin erosions should be covered with a non-adhesive sterile covering, and hypothermia should be avoided at all costs, particularly in the prehospital situation. The hypercatabolic nature of TEN makes nutritional supplementation essential for patients. Because enteral feeding reduces the chance of bacterial translocation, it is preferable to parenteral feeding. Nasogastric tubes might be utilised if the oral mucosa is significantly damaged. Carefully assess the amount of energy and dietary support needed (target for 20 to 25 kcal/kg/day).
Wound Care
Prior to re-epithelialization, aseptic wound care is crucial to preventing subsequent infection. Mucosal lesions can take longer to heal than skin lesions, which typically do so in 2 weeks. For the treatment of wounds, there is no set method. There isn’t much solid data to support debridement of the afflicted skin either early, late, or not at all. Debridement of a wound should be performed while under local anaesthetic. Xenograft, allograft, & homograft are examples of biological dressings. Biobrane is an example of a biosynthetic dressing. Silver-impregnated dressing is another possibility. Additionally, effective wound care will lower the need for analgesics.
Infection is widespread and can be fatal. The most frequent infection is staphylococcal, accompanied by pseudomonas infection, which happens after a lengthy hospital stay. Antibiotics for prevention are not advised because the survival chances remain unchanged. To find and treat an early infection, skin lesions should, however, be microbiologically assessed on the day of presentation & every 48 hours. Skin swabs showing signs of infection, a patient’s condition rapidly deteriorating, or a fast drop in temperature are all indications that antibiotic treatment is necessary. Anaerobes, gram-positive and gram-negative organisms, and all of them should be covered with empirical antibiotics.
Pharmacotherapy
Systemic steroids, cyclosporin, plasmapheresis, TNF-alpha (anti-tumor necrosis factor-alpha), & IVIG (intravenous immunoglobulin) have all been tried without success. All of the clinical information that has been published on these drugs is anecdotal and based primarily on observational studies. It is very difficult to conduct high-quality randomized controlled studies to evaluate the effectiveness of these treatment approaches because TEN cases are so uncommon. Steroids administered systemically are frequently used to stop TEN cases from progressing.
However, several research connected steroids with a rise in mortality. Three days of daily plasmapheresis may help to further eliminate the harmful drug, its metabolites, & inflammatory cytokines. However, these findings are not supported by a prospective randomised trial. In afflicted keratinocytes of skin lesions, particularly in skin blisters, TNF-alpha is overexpressed. According to certain research, TNF- alpha inhibitors can cause skin lesions to heal quickly. When administered within the initial 72 hours, IVIG also demonstrated favourable benefits.
Complications
Ocular problems are frequent and occasionally significant. Immediate ophthalmological evaluation is essential, and topical lubricants or steroid drops, or antibiotics are frequently used as treatments. Genitourinary issues are also frequent. To encourage mucosal recovery, topical oestrogen is used.
Menstrual suppression may be useful in extreme situations to reduce the chance of developing vaginal adenosis. Other medical professionals, such as those in urology, otolaryngology, & pulmonary medicine, may be required to provide additional insight based on the clinical picture. All TEN patients should also be evaluated to see if they require psychological treatment after discharge.
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