Continuing Education Activity

Toxic epidermal necrolysis (TEN) is potentially life-threatening acute mucocutaneous Syndrome. It usually occurs because of inappropriate immune reactions to certain drugs. It is characterized by keratinocyte necrosis with separation of the epidermis from the underlying dermis. TEN is rare (1.9 per million adults per year in the United States). However, its mortality rate is high (30% of cases). Prompt recognition of cases and stoppage of the offending drug and referral to burn unit is the mainstay of treatment. This activity will review the evaluation and management f TEN cases and highlight the importance of an interprofessional team approach in evaluating these cases.

Objectives:

• Describe the pathophysiology of toxic epidermal necrolysis (TEN).
• Explain the most common clinical features of TEN.
• Differentiate between TEN and other exfoliative skin conditions, including Steven-Johnson Syndrome (SJS).
• Identify the importance of early intervention and describe different treatment options.

Introduction

Toxic epidermal necrolysis (TEN) is a potentially life-threatening condition characterized by extensive exfoliation of the epidermis and mucous membrane, which may result in sepsis and death. It was initially described by Alan Lyell in 1956 as “an eruption resembling scalding of the skin."[1]

In most cases, TEN occurs as a consequence of an immune reaction to certain drugs. Nevertheless, infection, tumors, and vaccination have been reported as potential causes. Steven-Johnson Syndrome (SJS) shows the same disease process and is considered to be in the same spectrum of drug-induced epidermolysis. The main difference is the extent of skin detachment. TEN usually involves more than 30% of the total body surface area, while SJS affects less than 10%.[2]

Etiology

TEN can be induced by medications, infections, vaccines, or even idiopathic. Reaction to certain drugs is by far the most common cause. Various medications have been linked to TEN, including antibiotics (sulfonamides, chloramphenicol, penicillins, and quinolones), antiepileptics (barbiturate, carbamazepine, phenytoin, valproate, and lamotrigine), non-steroidal anti-inflammatory drugs (NSAID), especially oxybutazone and piroxicam, antiviral drugs (oseltamivir and abacavir), and allopurinol. According to the 2008 Euro-SCAR study, the drugs with a high risk of TEN are lamotrigine, carbamazepine, phenytoin, nevirapine, phenobarbital, sulfonamide, sulfasalazine, allopurinol, and oxicam-NSAIDs.[3][4][5] Most of the cases present within the first 4 weeks of the initiation of the treatment.[6]

Other potential etiologies include infections such as mycoplasma pneumoniae, hepatitis A and human herpesvirus 7, malignancies such as hepatocellular carcinoma and lung cancer, and vaccination especially meningococcal vaccine.[7][8][9] More recently, TEN has been reported in COVID-19 patients due to either the viral infection or the medications used in the course of treatment.[10][11]

Epidemiology

The estimated incidence of TEN in the United States is 1.9 per million adults per year, while SJS affects around 9.3 per million people per year.[12] Worldwide, there are numerous reports. In 1996, a German study estimated the yearly prevalence per million of both SJS and TEN cases to be around 1.9.[13] The reported figure for both SJS and TEN cases in the United Kingdom between 1995 and 2013 is as high as 5.76 cases per million inhabitants per year.[14] While in Japan, TEN affects around one patient per million adults per year.[15]

Most studies report that Asian and black patients are more susceptible compared to the white population. Some studies report a two-fold risk increase in the Asian and black populations. There is a clear female sex predilection with a female to male ratio of 1.5 to 1.[16] The majority of patients with TEN are between the 5th and7th decade of life. However, it can affect any age group. In general, adult cases are mainly drug-induced, while infections are the main cause in children.[12] Many recent studies highlighted the association between different HLA alleles and the development of TEN, especially in the Southeast Asian population.[17][18][19]

Pathophysiology

TEN was previously considered to be related to Fas-Fas ligand or granulysin-mediated apoptosis. More recent studies suggested the reactive oxygen species (ROS) as the initiating factor for keratinocyte damage and that it precedes the activation of the beforementioned apoptotic systems.

Fas is a membrane-bound protein responsible for the initiation of programmed cell death through a series of intracellular events. Fas ligand (FasL), which is usually produced by cytotoxic T(CTL) cells and natural killer (NK) cells, tends to bind to Fas on target cells, initiating apoptosis. The fact that the number of these cells is low in skin biopsies taken from TEN patients indicates that they are not the source of FasL.[20] Virad et al. study in 1998 found a high level of keratinocyte localization of FasL. This suggests that keratinocytes may be responsible for their own death.[21] Granulysin is a pro-apoptotic protein that was also detected in TEN blisters. It is one of many cytotoxic molecules secreted by CTL and NK cells that lead to cell-mediated cytotoxicity.[22] 

Oxidative stress is one of the proposed theories of TEN. Glutathione S-transferase-p (GST-p) is a biomarker of oxidative stress in keratinocytes. A higher level of this marker has been detected in TEN patients compared to other cutaneous drug reactions.[23] The culprit drug may interfere with the detoxification pathways resulting in the accumulation of reactive oxygen species (ROS), triggering programmed cell death.[24]

Histopathology

TEN is characterized by extensive full-thickness epidermal necrosis with subsequent epidermal detachment. There is little evidence of dermal or epidermal inflammation, as few mononuclear cells can be seen in skin biopsies. In the early stage, satellite cell necrosis occurs, which then progresses to extensive eosinophilic necrosis. Histological evaluation includes immunofluorescence analysis of the skin specimen to differentiate it from other exfoliative skin conditions.[25]

History and Physical

Most cases of TEN are drug-induced, and it usually occurs within 1 to 3 weeks of initiation of treatment. Therefore, a detailed medication history, especially one recently started, is a pivotal part of the patient’s history. Nevertheless, around 5% of reported cases show no history of recent drug utilization.[6]

Most patients report a prodrome of influenza-like symptoms (fever, malaise, arthralgia, rhinitis, and headache), which may last between 1 to 21 days. Then, cutaneous eruption ensues as an ill-defined dusky erythematous macular rash and bullae, which then coalesces to form sheet-like blisters. These blisters can easily slough, leaving a characteristic moist denuded dermis. They usually start in the face, presternal area before affecting the whole torso. However, the scalp area remains spared in almost all cases. The pain usually precedes the vesicular eruption. Applying slight pressure on the epidermis leads to epidermal detachment from the underlying surface (positive Nikolsky sign). This is not characteristic for TEN cases as it can occur with other exfoliative skin conditions, e.g., autoimmune bullous skin diseases. The progression of the cutaneous eruption is highly variable. In most patients, it occurs over a period of 2 weeks. However, it can abruptly evolve to affect the whole body within 24 hours. In severe cases, it may also occur in areas of reepithelialization. Evaluation of the surface area of the affected skin is important to differentiate TEN from SJS. It is essential to emphasize that only detached skin (i.e., blisters or erosions) or the potentially detachable skin (Positive Nikolsky sign) should be included when calculating the affected body surface area.[26]

Mucosal affection (erythema and erosion) occurs in 90% of cases and generally precedes skin eruption by 1 to 3 days. The oropharynx, eye, and genitalia are the most frequently affected mucosal membranes. However, other areas have been reported, including the respiratory tract and gastrointestinal tract.[27][28] Respiratory involvement may lead to serious pulmonary disease even with a normal chest radiograph. Initial ocular affection is common and can range from acute conjunctivitis, eyelid edema, and erythema to more severe forms, including corneal ulceration.[29][30] The release of a massive amount of cytokines may lead to major metabolic disturbances, including sepsis, multiorgan failure, and gastrointestinal hemorrhage. This is the cause of the high mortality rate associated with TEN (30% of cases).[31]

Evaluation

TEN is a clinical diagnosis that is confirmed by early histological analysis of the affected skin. Early skin biopsy confirms the diagnosis and guides the treatment plan.  A frozen section may be helpful to expedite the diagnosis. Histological evaluation of the skin biopsy should include immunofluorescent analysis to differentiate TEN from other dermatological diseases. There are no specific blood tests to diagnose TEN. However, a basic screen including (complete blood count, erythrocyte sedimentation rate, coagulation studies, urea and electrolytes, and liver function) is essential to plan supportive treatment, detect organ failure, and assess the overall prognosis. Anemia and lymphopenia are common. However, the presence of neutropenia is an unfavorable prognostic factor.[32] 

Coagulation profile and blood count should be kept within the normal values, especially in patients with extensive mucosal affection, as this may put them at risk of severe bleeding, especially from the gastrointestinal system. Transfusion of blood or blood products may be considered in some cases.[16]

Imaging studies are not essential for the diagnosis of TEN. However, it can be used to assess complications such as chest radiographs in cases of pulmonary affection. Another useful test is the patch test which may be helpful to identify the causative agent in around 50% of patients.[33]

The score of TEN (SCORTEN scale) is a tool to assess the severity of illness and to predict mortality rate. It contains 7 independent variables assessed in the first 24 hours of presentation to the hospital, and it gives an indication of mortality rate. This includes the age of >40 years, heart rate of ≥120 beats per minute, presence of cancer or hematological malignancy, affected body surface area of ≥10% within the first day, serum BUN of >28 mg/dL, serum bicarbonate of <20 mEq/L, and serum glucose of >252 mg/dL.  According to these risk factors, a patient's mortality score can vary from 3.2% (if only one risk factor presents) to >90% (if 5 or more risk factors are present).[31]

Treatment / Management

The mainstay treatment of TEN is supportive care until re-epithelialization of the affected skin. Supportive measures include fluid resuscitation, pain management, wound care, and nutritional support. Early management of these cases in the emergency department should focus mainly on two things: discontinuation of the offending drug and early referral to a burn unit or intensive care unit with experience in dealing with such cases. When taken in the first 24 hours of blister formation, these two measures decrease infection rate and hospital stays and improve the overall survival.[34]

The airway should be observed frequently, along with the provision of supplemental oxygen via a face mask if needed. In case of respiratory distress, endotracheal intubation should be done by an expert. Fluid resuscitation using crystalloids should be guided by one of the standard burn resuscitation Performa (e.g., Parkland formula). The target of resuscitation should be to maintain adequate tissue perfusion by achieving an adequate mean arterial blood pressure (ABP>65mm Hg), a central venous pressure between 8 to 12 mmHg, and a urine output of 0.5 to 1 ml/kg/hour.[16][35] Pain management is extremely important to decrease patient’s distress. Opiates or patient-controlled analgesia (PCA) can be used. The non-adhesive sterile dressing should be used to dress areas of skin erosions, and care should be taken to prevent hypothermia, especially in the prehospital setting.[34]

Nutritional support is crucial in TEN patients due to the hypercatabolic nature of this disease. Enteral feeding is superior to parenteral feeding as it decreases the risk of bacterial translocation. If oral mucosa is significantly affected, a nasogastric tube may be used. Energy requirement and nutritional support must be carefully calculated (aim to 20 to 25 kcal/kg/day).[36][37]

Wound Care

Aseptic wound care is important to prevent secondary infection until re-epithelialization. Skin lesions usually heal within 2 weeks, while mucosal lesions may take longer. There is no standard approach for wound care. No strong evidence to support either early, late, or no debridement of the affected skin. In case of wound debridement, this should be done under general anesthesia. The involved area can be dressed by a variety of options, including biological dressing (e.g., allograft, xenograft, and homograft), biosynthetic dressing (e.g., biobrane), or silver-impregnated dressing. Good wound care will also reduce analgesia requirements.[38][39][40] 

Infection is common and may be lethal. Staphylococcal infection is the most common, followed by pseudomonas infection, which occurs after a prolonged hospitalization.[41] Prophylactic antibiotics are not recommended as there is no change in the survival rates.[42] However, a microbiological assessment of skin lesions should be done on the day of presentation and every 48 hours to detect and treat an early infection. Indications of antibiotic treatment would be evidence of infection in skin swabs, rapid deterioration of the patient's condition, or sudden drop of patient’s temperature. Empirical antibiotics should cover gram-positive and negative organisms along with anaerobes.[34]

Pharmacotherapy

There is no proven effective treatment modality, including systemic steroid, plasmapheresis, cyclosporin, Anti-tumor necrosis factor-alpha (TNF-alpha), or intravenous immunoglobulin (IVIG).[26][43] All the reported clinical data regarding these medications are anecdotal and mainly based on observational studies. The rarity of TEN cases makes it extremely challenging to achieve high-standard randomized controlled clinical trials to test the efficacy of these treatment modalities. Systemic steroids are commonly used to halt the progression of TEN cases. However, some studies linked steroids to increase mortality incidence. Daily plasmapheresis for 3 days may enhance the elimination of the causative medication, its metabolites, and inflammatory mediators. However, there is no prospective randomized trial to support these findings.[44] TNF- alpha is overexpressed in the affected keratinocytes of skin lesions with a high concentration in skin blisters. Some studies report early resolution of skin lesions with TNF- alpha inhibitors. IVIG also showed encouraging results when started within the first 48 to 72 hours.[45]

Complications

Ocular complications are common and sometimes serious. Early ophthalmological consultation is vital, and treatment usually consists of topical lubricants, antibiotics, or steroid drops. Genitourinary complications are also common. Topical estrogen is used to promote mucosal healing. In severe cases, menstrual suppression may be helpful to minimize the potential risk of vaginal adenosis. According to the clinical presentation, further input may be needed from other specialists, including urology, otolaryngology, and respiratory medicine. Furthermore, all patients with TEN should be assessed for the need for post-discharge psychological support.[34]

Differential Diagnosis

Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) are in the same disease spectrum. The only difference is the severity of skin affection. If epidermal detachment is less than 10% of the total body surface area, it is SJS. While if the affected body surface area is more than 30%, this is considered TEN. Overlap between the two conditions occurs when the affected body surface area is between 10 to 29%. The main differential diagnosis is erythema multiform major (EMM). It mainly affects less than 10% of body surface area and is characterized by the symmetric acral distribution of target lesions with or without blister formation. In contrast, SJS and TEN consist mainly of skin blisters arising on erythematous macules in central distribution (face and trunk). Moreover, 2 or more mucous membranes are involved in 90% of SJS and TEN cases.

Other differential diagnoses include:[46]

• Other drug rashes
• Toxic shock syndrome(usually present with early multiorgan failures and unique cutaneous manifestations in the form of macular rashes affecting palm and soles that later on evolve to desquamation over the period of 14 days)
• Paraneoplastic pemphigus(as a mucocutaneous manifestation of malignancy)
• Exfoliative erythroderma(usually affects skin only and spares mucous membrane and is painless in most of the cases)
• Staphylococcal scalded skin syndrome in children: (evidence of staphylococcal infection, no history of drug intake, and it usually spares mucus membranes)

 Skin biopsy is also an important tool to differentiate TEN and SJS from these disorders.

Prognosis

The reported mortality rate of TEN cases is 25 to 30% compared to 1 to 5% in SJS cases. The prognosis of TEN cases depends on the degree of cutaneous affection.[47] The higher the affected body surface area, the higher the mortality rate.[26][48] Infection is the main cause of death. Other potential lethal complications are adult respiratory distress syndrome, pulmonary embolism, renal and cardiac failure, and gastrointestinal bleeding.[49]

As discussed before, the SCORTEN, formalized by Bastuji-Garin et al., is a valid method for assessing the disease severity and the survival rates of each patient. It is based on 7 variables that need to be evaluated within the first 24 hours of hospital admission. These variables include age, affected body surface area, heart rate, presence of malignancy, serum urea, glucose, and bicarbonate.[31]

Complications

Several complications can occur in TEN patients because of the extensive cutaneous and mucosal membrane involvement. In the early stage, the presence of painful stomatitis may interfere with oral intake with an increased risk of dehydration. Loss of the epithelial barrier increases the risk of infection and septicemia. This may evolve to septic shock and multiorgan failures.[41] In the long term, the involved skin may show signs of hypo or hyperpigmentation, while the affected mucosal surfaces may heal by stenosis and strictures. In females, vulvovaginal involvement is common and can lead to stenosis, vulvar adenosis, and dyspareunia. In men, phimosis is the most common complication.[50]

Ocular complications are one of the most common and serious sequelae of TEN. Therefore, early ophthalmological consultation is advisable in such cases. Corneal ulcer, xerophthalmia, meibomian gland dysfunction, panophthamitis, or even blindness are some of the reported complications.[29] Respiratory complications include pulmonary embolism, adult respiratory distress syndrome (ARDS), and pneumonia.[51] Gastrointestinal complications in the form of extensive bleeding from the affected mucosa, gingival synechia, and xerostomia due to affection of the salivary glands.[52]

Deterrence and Patient Education

It is mandatory to inform patients who have been previously diagnosed with TEN to avoid any future use of the causative drug and any medication from the same class as cross-reactivity is reported.[53] All patients should be educated on sun safety and the use of sunscreen to prevent post-inflammatory pigmentary changes. Some of the patients may need long-term psychological support, and this should be evaluated for all the patients before discharge from the hospital.[54]

Enhancing Healthcare Team Outcomes

Management of TEN cases should be done in an interprofessional team approach to ensure the best outcome. Early transfer to a burn facility or intensive care unit with experienced staff in dealing with complex wounds, fluid resuscitation, and mechanical ventilation improves the overall survival of these patients. Dermatologists have a vital role in identifying and managing these cases.

Plastic consultation is also important to assess the need for debridement of necrotic skin areas. Moreover, the early involvement of ophthalmologists is essential to decrease long-term ocular complications. The respiratory specialist may be needed to assess the need for a pulmonary toilet in cases of pulmonary sloughs. Other specialties such as otolaryngology and urology may also be involved. Additionally, the involvement of the dietitian and physiotherapy team is imperative to optimize the nutrition and mobility of the patient.[34][55][35] [Level 2]