This research paper will be an in-depth description of Toxic Epidermal Necrolysis (TENS) Syndrome, focusing on its pathophysiology, epidemiology, the various diagnostic measures, diagnosis, and its evaluation and management.

by eliazarkim462gmailcom (student)

University Degree Medicine and Dentistry

Introduction

Toxic Epidermal Necrolysis (TENS) Syndrome is a severe dermatologic disorder resulting from adverse drug reactions in the body. According to Barvaliya et al. (2011), the elderly aged above 70 are at more risk of developing Toxic Epidermal Necrolysis complications. However, other risk factors such as a compromised immune system, malignancies, viral pneumonia, and autoimmune conditions may make even the younger individuals susceptible to TENS Syndrome. Toxic Epidermal Necrolysis Syndrome is an advanced case of Stevens-Johnson Syndrome caused by a reaction to drugs such as antibiotics and anticonvulsants. As a result, there is a 20% increment in skin involvement from Stevens-Johnson Syndrome (10%) to TENS syndrome (30%). As a result, the condition causes widespread erythema, skin necrosis, and detachment of the epidermal layer from the mucous membranes, compromising skin integrity. All these symptoms are life-threatening and may result in death. Therefore, early diagnosis and aggressive treatment are essential in the management of the condition. This research paper will be an in-depth description of Toxic Epidermal Necrolysis (TENS) Syndrome, focusing on its pathophysiology, epidemiology, the various diagnostic measures, diagnosis, and its evaluation and management. Finally, the paper will highlight the important role of the nurse practitioner in the management of patients affected by the condition, employing the Shuler Framework.

Pathophysiology

The exact mechanism of the genesis of Toxic Epidermal Necrolysis Syndrome has not been fully explained. However, various theories have been proposed to explain the pathogenesis of the condition, many having gained worldwide acceptance. Initially, Fas or Granulysin-mediated apoptotic processes were identified as the pathomechanism behind the etiology of TEN syndrome. Recently, there have been developments in the studies of the condition's pathophysiology, resulting in the proposition of another pathway system, the reactive oxygen species (Ros), to explain the mechanism of TEN Syndrome. They all attempt to explain how apoptosis is induced in the epidermal cells, an accepted TEN Syndrome mechanism.

Fas-mediated Apoptosis

Fas is a membrane-bound protein expressed in almost all cells. Its activation results in the activation of caspases, which in turn induce apoptosis. The natural ligand to the Fas protein is the Fas ligand produced by the natural killer cells and the cytotoxic T lymphocytes. The successful binding of the Fas ligand (FasL) to its receptor has been determined to induce keratinocyte apoptosis. The high concentration of the Fas ligand in the keratinocytes was revealed by immunostained sections of the skin tissue acquired from patients. Therefore, it was proposed that the Fas ligand has a role in the mass destruction of keratinocytes in patients with TEN Syndrome.

Granulysin Cell-Mediated Apoptosis

Granulysisn serves as a pro-apoptotic protein that can affect apoptosis without direct cell-cell contact. Chung et al. identified the activity of these proteins in 2008 following an initial disregard of all the proposed mechanisms involving cell-mediated immunity due to poor infiltration of the cells in the epidermal tissue of the patients. However, Chung's findings and conclusions concerning the role of granulysin protein gained popularity and acceptance after a series of pieces of evidence was presented. Therefore, granulysin has been identified as one of the initiators of apoptosis of the keratinocytes by their cytotoxic activity. Actually, it is a direct determinant of the severity of the condition in patients with TEN Syndrome.

Reactive Oxygen Species

Oxidative stress is a possible cause of intracellular keratinocyte damage, and therefore a possible mechanism for the development of TEN. Impaired detoxification pathways result in the production of the reactive oxygen species. This is toxic to cells and results in the destruction of the cell membrane and major cell activities to the extent that the cells are eliminated by apoptosis via the natural mechanism of FasL and tumor necrosis factor. The GST-π is often used as an indicator to confirm the evidence of oxidative stress in the epidermal cells in TEN. Tissue necrosis factor α (TNF α) is thought to be responsible for producing the reactive oxygen species. It impairs the electron transport chain by a progressive increase in nitric oxide production in the mitochondria. The impaired transport chain subsequently lessens the detoxifying ability of the mitochondria and thus the accumulation of the reactive oxygen species that is lethal to the cells.

Additional to the mentioned proposed mechanisms, other theories include alternative cell-mediated apoptotic pathways that do not involve the protein granulysin and cytokine-induced enhancement of the apoptotic pathways. As aforementioned, the generally accepted pathomechanism of TEN Syndrome is by the apoptotic killing of the epidermal cells and the keratinocytes. Therefore, all these theories try to explain the exact processes that result in induced apoptosis.

Epidemiology

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Epidemiology

TEN is a rare condition with an incidence of 0.4-1.2 per million persons annually. More women are affected than men, in the ratio of 1.5: 1 (French, 2006). The incidence of occurrence of TEN progressively increases with an increase in age. However, the age of acquisition of TEN is dependent on other factors that directly affect the individuals. Individuals with an immunocompromised system such as those affected with lymphomas and HIV, those with brain tumors, and under radiotherapy are particularly at more risk of acquiring TEN.

Reaction to drugs during their therapeutic application, especially antibiotics and anticonvulsants, is highly linked to the current incidences of TEN. Examples of such antibiotics include aminopenicillins, quinolones, and cephalosporins. The risk of development is highest during the first week of therapy with the mentioned drugs. The anticonvulsants have a longer half-life with a protracted duration of action, and therefore the risk of the onset of TEN is highest within the first two months with a likelihood of fatal outcomes. Additionally, immunizations and infections can be a cause of TEN. According to French (2006), therapeutic drugs are reported as a cause of the condition in 95% of the cases. The mortality rate of TEN is 30%.

Clinical Features and Profile

A review conducted by Letko et al. confirmed the occurrence of common symptoms in all the affected individuals 2-3 days before the appearance of the skin rashes. These symptoms resemble upper respiratory tract infections and may sometimes be confused with respiratory tract infections, e.g., rhinitis and anorexia. Additionally, other prodromal signs such as pruritis may appear just before the onset of the acute phase of TEN syndrome, lasting from about a day to 3 weeks.

The occurrence of persistent fever, shedding off the epidermal layer, and mild mucositis characterize the acute phase. During this phase, the skin lesions start to appear as small painful swellings that begin on the facial thoracic and thoracic regions and then systematically spread to other parts of the body. This may last for about 8-12 days. Epidermal sloughing may spread to other sites of the body, including the epidermal lining of body cavities such as the pharyngeal, esophageal, anal, and vaginal cavities.

Diagnostic Measures

Several measures can be used as a diagnostic criterion for TEN Syndrome. Granulysisn, for example, can be used as a marker for the early diagnosis of TEN. It is a protein that accumulates in the epidermal cells of TEN patients. Therefore, an enzyme-linked immunosorbent assay can be used to detect the presence of this protein for early diagnosis. As mentioned earlier, TEN is a severe case of SJS and could sometimes be confused. Therefore, the surface area of epidermal detachment is used to differentiate between the two, i.e., less (10%) for SJS and more (30%) in TEN. Other important diagnostic measures include the presence of acantholysis (epidermal detachment and blister formation), diarrhea in patients with TEN dissemination to the GIT, erythema, and persisting fatigue.

Diagnosis and Diagnostic Methods

Diagnosis of TEN relies on the observable clinical features as well as the histological manifestations of the wound exudates and the keratinocytes. Clinical signs such as erythematous swellings on the skin and detachment of the epidermis are typical of TEN Syndrome. A positive Nkolsky sign for the erythematous swellings is a confirmative test for TEN. Histological analysis of collected specimens is more specific and can be used to rule out other possible conditions similar to TEN. Formalin-fixed skin sections obtained by biopsy reveal necrosis on the epidermal layers and confirm the condition.

Moreover, differential diagnoses are conducted to confirm the cause of the condition. For instance, staphylococcal scalded skin syndrome was used in the past to confirm TEN resulting from staphylococcal infections. It was, however, abandoned due to a marked decrease in the incidence of the TEN conditions with this particular cause. Furthermore, fixed bullous drug eruptions can be employed as a differential diagnosis. These drug eruptions are characterized by adverse drug reactions that result in the formation of bullae (fluid-filled swellings), typical of TEN cases resulting from drug interactions.

Furthermore, the role of linear IgA dermatosis in the differential diagnosis is also worthy of mentioning. It is an accumulation of immunoglobulin A at the dermo-epidermal junction and is drug-induced. It can therefore be diagnostic of drug-induced TEN. Lastly, paraneoplastic pemphigus, a mucocutaneous disease of autoimmune origin, can be used for performing a differential diagnosis for TEN Syndrome.

Management of TEN Syndrome

One study conducted by Lissia, Mulas, Bulla, & Rubino (2010) suggested that for effective medical management of TEN to be realized, a multidisciplinary approach must be applied. This includes a rapid diagnosis to identify the precise cause and an immediate withdrawal of the suspected causative drug and the use of the most appropriate supportive care and individualized therapy. Therefore, an early and accurate diagnosis is an important step in the process of medical management of TEN. In their study, Lissia et al. (2010) proposed the following as a part of the management:

General Measures in Management

This is an initial treatment that focuses on the clinical effects resulting from the compromised integrity of the skin and other generalized symptoms. Due to a large-scale skin detachment, the patients experience severe water, protein, and electrolyte loss, leading to dehydration. These symptoms are typical of burns, and therefore their management resembles that given to burn patients in the burn units.

After identifying and discontinuing the causative drug, the patients are started on fluid and electrolyte replacement as the first line of treatment. Additionally, regulation of metabolic equilibrium, acid-base balance, glucose, and serum protein control is made to stabilize the patient. Letco et al. (2005) supports these stabilization measures as a key management step and states that an immediate intravenous fluid replacement with crystalloids is critical, even though studies from other authors are contradictory. Moreover, patients with difficulty in taking food orally are assisted by Total Parenteral Nutrition (TPN). The patients lose high levels of protein and other nutrients via the wound exudates. Therefore, additives of Nitrogen and all the essential nutrients are included in the TPN. According to Windle (2005), arginine, omega three fatty acids, and glutamine should also be supplied in immune-modulating artificial nutrition support. These, however, need to be carefully administered with close monitoring of the effects.

In addition to nutritional requirements, the patients are also considered critically ill, and therefore, analgesia, prevention, and patient immobilization are done to reduce pain.

Wound Management

Wound management is an important treatment procedure for the reduction of mortality rates. It aims to protect the wound from infection by disease-causing microorganisms, providing an ideal physiological environment to allow re-epithelization and minimizing frictional movements. Two approaches may be used when managing the wounds, i.e., a conservative procedure to withdraw all the exudate from the wounds and replenish the sloughed epidermis with another one, or surgical removal of the wound debris followed by dressing to enhance healing. The topical application of a suitable cream is used to prevent infection, although their use is selective depending on patient factors. For example, the silver sulfadiazine cream is only applied to patients without a history of hypersensitivity to sulphonamides.

Moreover, wound management involves dressing the wounds using various materials such as the synthetic skin substitute Biobrane. AQUACEL has gained global fame and uses its cost-effectiveness and outstanding benefits to patients with up to 86% skin detachment (Huang et al., 2008). All these wound management practices are done to alleviate pain, improve re-epithelization and enhance healing.

Pharmacological Treatment

Complete withdrawal of the suspected causative drug is considered the first approach in the therapeutic management of TEN. The various proposed mechanisms of pathogenesis have been exploited for the development of the various already present treatments. However, new studies of the effects of these treatments have resulted in the withdrawal of some. For example, corticosteroids were used for their anti-inflammatory properties but were later discouraged due to the increase in other infections due to their continuous use. Cyclophosphamide's ability to induce apoptosis in immunocytes after conversion to aldophosphamide in the liver makes it a potential drug for the treatment of TEN Syndrome. Cyclosporin also has an immunosuppressive activity on the T lymphocytes, blocking the apoptotic cascade, a significant pathomechanism for TEN. Thalidomide is another drug that targets the process of release of TNF α from monocytes but is withheld due to its high level of teratogenicity.

Plasmapheresis

This involves the removal of whole blood from the patient and reinfusion with new plasma. It helps reduce the inflammatory mediators and the causative drug, improving the survival chances of the patients.

Intravenous Immunoglobulin

This was developed in line with the proposed mechanism of Fas-mediated apoptosis of the keratinocytes. It blocks the lytic activity of the Fas ligand by competitive inhibition by the Fas-binding antibodies included in the intravenous immunoglobulin infusions. An initial study conducted by Viard et al. in 1998 on ten patients revealed this treatment approach to be effective.

Evaluation of Treatment Outcomes

In patients treated with plasmapheresis, the effectiveness of the treatment is assessed by patient improvement after the initiation of treatment. After three days of the initiation of treatment, a better prognosis of plasmapheresis is indicated by a stoppage in blister formation. This was followed by a general improvement of the symptoms of the patients. However, re-epithelization may delay depending on the severity of the condition and patient age. Re-epithelization in younger patients tends to be faster than in the elderly. Plasmapheresis also helps to reduce the concentration of the “culprit” drug; hence a positive prognosis involves a marked reduction in the concentration of the causative drug. Progressive improvement of the clinical features and laboratory values is also indicative of the effectiveness of pharmacological therapy.

On the other hand, intravenous immunoglobulin treatment serves to accelerate the process of healing dramatically, and thus the time is taken for patient healing. As a result, patients treated with IVIG can be assessed for positive response by considering the healing time. Nonetheless, the improvement of the patients is highly dependent on patient age and the severity of the disease.

Role of the Nurse Practitioner in Patient Management

The Shuler Model of nurse practice incorporates a multidisciplinary approach to care for the patients’ needs and the affected family as well. TEN Syndrome nurse practitioners assess, manage and evaluate the care of TEN patients in the burn units and the intensive care units. As mentioned earlier, patients with toxic epidermal necrolytic syndrome suffer a skin destruction condition similar to burn patients. Therefore, in addition to other individualized treatments, they receive care like that of burn patients. It is also worthy of mentioning that TEN affects the individual patient and affects the entire family. Consequently, the nurse practitioner actively plays a role alongside other medical personnel such as therapists, pharmacists, and doctors in patient treatment.

The nurse practitioner dresses the wounds using the most appropriate wound dressers and administers the correct dosage of the pharmacological drugs under the doctor's command in charge. They also actively participate in monitoring the treatments and patient response to the administered drugs and therapy. Furthermore, they evaluate the effectiveness of the form of the treatment being administered and report any adverse effects observed. Nurses also play a role in helping the family understand the condition of the patient, better and cost-effective treatment procedures that can be employed, and psychological help to aid in family acceptance of their family member's condition. Lastly, they are involved in health promotion by educating family members on the risk factors of TEN Syndrome, when to seek medical intervention, and avoiding the possibly avoidable risk factors. All these roles help the affected patient, comfort their family, and reduce the incidence of occurrence.

Conclusion

In summary, Toxic Epidermal Necrolytic Syndrome is a rare condition that affects all population ages depending on susceptibility and underlying factors. Women are more vulnerable to the condition than men due to physiological differences. There has not been a standard established mechanism of the disease, but several theories described above have been proposed to explain the pathophysiology. Treatment procedures are based on the concepts of these various theories, and they aim to block the apoptotic pathways and promote re-epithelization. Despite there not being accurate treatments for TEN, an early diagnosis followed by an integrated treatment approach can be very important in reducing mortality rates.

References

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