INTRODUCTION

Toxic Epidermal Necrolysis (TEN) is a rare life-threatening drug reaction characterized by the extensive destruction of keratinocytes, leading to desquamation of the epidermis and mucosal epithelium with the formation of blisters and extensive erosions [1]. Skin symptoms are preceded by fever and signs of malaise. The disease is rare, with reports ranging from 2 to 7 cases per million people yearly [2]. Medications are the most common trigger for this condition and usually cause the illness within 8 weeks of admission, in both adults and children [3]. The diagnosis is made based on the clinical presentation and the level of skin involved. If affected, is less than 10% of the skin of the whole body the authors refer to the condition as Stevens–Johnson syndrome (SJS), whereas above 30% of the skin is referred to as TEN. With patients having 10–30% of their skin involved it is considered a syndrome of overlap between SJS and TEN [4]. Epidermal loss leads to a water-electrolyte imbalance, hypoalbuminemia, impaired thermoregulation of the body and an increased risk of infection hence the mortality rate for TEN is 50% and for SJS is 10%, with a combined rate of 30%, the most common causes being sepsis and pneumonia [3]. There are no explicit drug treatment protocols in the available literature; evidence to date suggests that the outcome of patients with TEN, is largely dependent on prompt withdrawal of the causative agent, followed by supportive care and appropriate wound care [5]. Patients should be treated with extensive fluid therapy, along with 24-hour monitoring of vital signs and control of water-electrolyte balance. The following paper presents 3 patients hospitalized with TEN and provides a narrative review of the management of this condition.

CASE’S DESCRIPTIONS

Case 1

The patient a 47-year-old woman with a history of skin rash in the cleavage area spreading to other parts of the body accompanied by fever and enlargement of the cervical lymph nodes was admitted for diagnosis and treatment. The patient due to the condition had previously been administered amoxicillin 1 g/day, followed by dexaven 8 mg two times. When taking a medical history, it was revealed that 3 weeks earlier, the patient started treatment with lamotrigine 50 mg/d. In the physical examination, the skin of almost the whole body presented maculopapular rash/exanthema, locally visible epidermal desquamation, on the feet, well-tight serous blisters, and erosions on the mucous membranes of the oral cavity (Fig. 1). In laboratory tests: slightly decreased total protein (5.7 g/dL), elevated CRP (12.64 mg/dL), elevated fasting glucose (110 mg/dL), elevated liver markers: ALT (102 U/L), AST (71 U/L), moreover, the morphology of blood presented a small neutrophilia, monocytosis, eosinopenia. Due to the involvement of ulceration in the oral cavity, as well as sore throat and blurred vision, the patient was consulted with laryngology and ophthalmology specialists. On ophthalmologic examination of the anterior segment of the right and left eye: the eyeball was slightly irritated, the conjunctiva was blood-stained, and there was purulent secretion in the conjunctival sac and on the eyelashes. On laryngological examination, an ulceration was present in the nasal cavity on the septal mucosa on the left side, multiple ulcerations on the mucous membranes of the oral cavity, tongue and middle pharynx, as well as a slight loss of the epiglottal margin mucosa. On the SCORTEN scale, the patient obtained two points: 1 point for age and 1 point for epidermal separation covering > 10% of the body surface area (BSA). The mortality rate for this patient was therefore 12.2%. Lamotrigine, which was an exacerbating factor in the condition, was discontinued and the treatment has been started including dexaven i.v., cyclosporine 250 mg/day (4 mg/kg) and topical ointments containing 1% hydrocortisone, a bandage containing 0.5% chlorhexidine acetate solution, cholesterol ointment, and ointment containing hydrocortisone, natamycin with neomycin. In addition, a skin spray containing neomycin and dexamethasone was used. To relieve pain and other discomforts associated with ulceration of the oral cavity and middle pharynx, the patient was advised to rinse the mouth and throat with diclofenac solution, additionally take vitamin-containing chewable capsules, and for regeneration of the mucous membrane of the nasal cavity, a nasal spray containing D-panthenol and vitamin A + E was used. Due to the patient’s complaint of blurred vision and purulent discharge in both eyes, the patient was treated with the antibiotic gentamicin 0.3% in the form of drops administered directly into the conjunctival sac. However, the applied treatment did not bring improvement. Due to the patient’s worsening condition, immunoglobulins in a total dose of 130 g were implemented into the treatment, after which a significant improvement in the skin condition was obtained. The patient, in generally good condition, was discharged from the hospital after 10 days with recommendations to maintain treatment with cyclosporine and topical treatment of the lesions.

Figure 1. Maculopapular rash on the day of admission (A); erosions in the oral cavity (B); epidermal detachment (C), skin condition after the implemented treatment (D)

Case 2

The patient is a 61-year-old male transferred from the anaesthesiology clinic to the department of dermatology for treatment of skin lesions located on the trunk and extremities. The lesions had an erythematous character, with the presence of blisters that detached at contact (Fig. 2). The condition occurred suddenly, 2–3 days ago before admission, followed by a fever of up to 39°C. The patient denied other signs of possible infection. Through the patient’s medical history, a discovery had been made of an episode of cutaneous adverse reaction after carbamazepine intake in 2015 in the form of generalized drug-induced drug-induced dermatitis. Concomitant diseases were as follows: hypertension, hypercholesterolemia, hypothyroidism, schizophrenia, and mild mental retardation. On admission, the test for SARS-CoV-2 virus was positive. Laboratory tests revealed decreased haemoglobin (12.4 g/dL), erythrocyte count (3.79 × 10^6/μL) and haematocrit (36.2%). The tests also revealed thrombocytopenia (103 × 10^3/μL) and a significantly elevated C-reactive protein level (151.60 mg/dL). Also above normal were procalcitonin (6.21 ng/mL), D-dimers (4221 ng/mL), serum creatinine (1.37 mg/dL), phosphate kinase activity (1119.0 U/L). Antinuclear antibody (ANA) titters were determined — 1:320 granular luminescent type, in the specification of Mi-2 +, PM-Scl-75 (+), SRP +, Ro-52 +. Levels of tumour markers (AFP, CA 19-9, CEA, PSA) were normal. The blood cultures performed were negative. In accordance with the SCORTEN, the patient received 2 points, 1 point for age over 40 and 1 point for the initial area of epidermal detachment, which covered more than 10% of the body surface. These prognostic factors resulted in an estimated mortality rate for this patient of 12.2%. The patient proved difficult to manage due to his schizophrenia as the intravenous and intra-arterial catheterizations that had been placed continued to be removed by him. The patient was consulted by a psychiatrist, and a decision was made to discontinue ValproLEK (sodium valproate, valproic acid), as it was likely inducing epidermal necrolysis. Due to the unclear aetiology of Lyell’s syndrome (risk of possible infectious aetiology), systemic corticosteroid therapy was refrained from. Treatment was limited to topical steroid therapy with hydrocortisone spray. Additional body lubrication with cholesterol ointment along with vitamin A and hydrocortisone ointment for skin lesions on the limbs and trunk was applied to erosions. Intensive fluid therapy was administered, with 24-hour vital signs and fluid balance monitoring. As the treatment was not effective, the final decision was made to include intravenous immunoglobulins. A total of 170 g of intravenous immunoglobulin (IVIG) i.v. was administered after which improvement has been noted. The patient was discharged home in good general condition with recommendations for further treatment and follow-up.

Figure 2. Massive erosions and epidermal detachment

Case 3

The patient is a 59-year-old man admitted due to extensive erythroderma that appeared 2 days before admission to the Department of Dermatology. The patient was transferred from the infectious diseases ward where he was hospitalized due to alcoholic cirrhosis of the liver. Before admission, no new medications were introduced. During the stay the following drugs were administered: ciprofloxacin, amoxicillin, metronidazole, spironolactone, ramipril, amlodipine, furosemide, pantoprazole and thiazolidine carboxylic acid. There was suspicion that amoxicillin caused the reaction however other drugs couldn’t be ruled out. History of oedema of the lower extremities for many months, hypertension, alcoholic cirrhosis, oesophageal varices without bleeding, chronic gastritis, gastric ulcer with no mention of bleeding, diverticular disease, unspecified hyperglycaemia, anaemia, secondary thrombocytopenia and aortic stenosis. During hospitalization in the dermatology department, on admission, tests showed increased liver necrotic parameters (ALT 414 U/L, AST 294 U/L), increased total bilirubin (11.03 mg/dL), decreased albumin (2.5 g/dL), elevated creatinine (1.34 mg/dL), elevated ammonia (150 ug/dL), mild normocytic anaemia (Hgb 12.8 g/dL), hyperglycaemia (206 mg/dL) with a decrease in Hgb to 11.1 g/dL, WBC 5.23 thousand/μL. Total bilirubin increased to 16.79 mg/dL, hyperuricemia 183 ug/dL, AST 170 U/L ALT 244 U/L, hypoalbuminemia 2.2 g/dL. With reduced coagulation parameters INR 6.6 and thrombocytopenia PLT 16,000/μL. During hospitalization, the patient’s condition worsened. In physical examination, the patient was connected to a ventilator without any contact, even visual. The patient obtained four points on the SCORTEN scale: point for age over 40; peeling of the epidermis covering > 10% BSA on admission, serum urea > 10 mmol/L, bicarbonate < 20 mmol/L. This means that this patient has an estimated 58% mortality rate for TEN. The entire surface of the body was peeling skin, oozing and giving off a very unpleasant smell (Fig. 3). It was unclear which drug could have caused the patient’s reaction, thus most of the drugs were temporarily discontinued. Dexamethasone, vancomycin, and albumins intravenously along with topical therapy were implemented. Additionally, hypoglycaemic treatment was required. Skin condition gradually deteriorated as well as the patient’s general condition resulting in cardiac arrest, after which vital functions were restored, however, the patient was maintained with a respirator. Based on the collected data and numerous specialist consultations, it was established that the patient is not eligible for liver transplantation as a causative treatment and further management should be focused on palliative treatment. Given the patient’s declining vital parameters, the heart arrested again and the patient passed away.

Figure 3. Extensive erythematous skin detachment (A, B)

DISCUSSION

There have been reported various triggers for TEN, amongst them infections (especially of Mycoplasma pneumoniae aetiology), contrast agents, herbs, vaccines, and idiopathic causes [3]. However, drugs without a doubt remain the most common trigger, especially antibiotics, and antiepileptic drugs followed by nonsteroidal anti-inflammatory drugs (NSAIDs), antiviral drugs, and allopurinol [6]. In the first case, the most likely triggering factor was lamotrigine, which is a phenyltriazine derivative, used in the treatment of epileptic seizures, and bipolar affective disorder. According to a 2008 study called Euro-SCAR, lamotrigine was among the drugs with a high risk of TEN [7]. Despite the existence of a correlation between SJS and antiepileptic drugs, the exact mechanism of this relationship has so far not been clarified. According to some investigators, an important role in this mechanism may be played by arsenic oxide metabolites formed during the degradation of antiepileptic drugs [8]. Moreover, available studies also suggest that women are more predisposed to skin reactions after antiepileptic drugs in comparison to men [9]. A similar clinical course to that presented by patient 1 was described by Kumar et al. [10], whose patient also developed TEN 3 weeks after using lamotrigine at 50 mg nonetheless in the case of the present patient thanks to IVIG treatment the treatment in ICU was avoided. As for patient 2, the medication that most likely led to the development of the disease was valproic acid which is an anticonvulsant drug commonly also used to treat manic episodes in bipolar disorder. Many described cases of SJS or TEN were caused by the intake of valproic acid although it’s worth pointing out that it happens mostly in combination therapy with another antiepileptic drug, most commonly lamotrigine or carbamazepine [11, 12]. There are also reports of SJS developing after using valproic acid in monotherapy, but these are less common [13]. In the case of patient 3, which was taking three different antibiotics: ciprofloxacin, metronidazole and amoxicillin, and each of these antibiotics has connections to SJS/TEN described in the literature. It is worth noting that the lowest number of described cases include the use of metronidazole as only a few cases have been reported [14]. On the other hand, amoxicillin is classified as one of the beta-lactam antibiotics which are considered to be one of the main causes of severe cutaneous adverse drug reactions. In a study conducted, by Kim et al. it was shown that SJS/TEN is more likely to happen when beta-lactam antibiotics are used in comparison to non-beta-lactam antibiotics [15]. The last of three is Ciprofloxacin, a fluoroquinolone group antibiotic that is a rare but determined cause of SJS [16]. Similar to patient 3 in the case presented by Cravens et al. whose patient a few days after the end of ciprofloxacin treatment, developed an itchy, blistering rash that covered 90% of his body surface [17]. Diagnosis is certain in the case of that patient as it was confirmed by biopsy.

There are two international guidelines for the treatment of TEN: one published by the British Dermatological Association and the other by the Indian Association of Dermatologists, Venereologists and Leprologists [18]. They emphasize discontinuation of suspected causative medications as soon as possible and initial assessment of the patient’s condition with calculation of SCORTEN within the first 24 hours of admission. Management of patients with TEN can best be carried out under sterile conditions in an intensive care unit or a special burn unit [19, 20]. British guidelines favour primarily local treatment and early involvement of a multidisciplinary team (including an anaesthesiologist, pulmonologist, dermatologist and ophthalmologists) [19]. Patients with SJS/TEN require multidirectional treatment since most have ocular involvement complications as well as oral and genital mucosal damage. Therefore, it is so important to cooperate with physicians from other disciplines, such as ophthalmology, otorhinolaryngology or anaesthesiology, and in cases that are not promising, to involve palliative medicine specialists. Mucosal lesions occur even in 90–95% of patients and in a third of them, mucositis may precede skin lesions by several days [21, 22]. Mucosal lesions most commonly affect the mouth, throat, eyes, and genitals along with the anus, and less commonly the nose, oesophagus, trachea and bronchi resulting in s acute respiratory distress, gastrointestinal distress, and genitourinary dysfunction and denudation [21, 22]. Acute ocular complications are reported in most patients with SJS/TEN. A study by Gueudry et al. [23] found that 74% of patients experienced ocular involvement during the acute phase of the disease [19]. Ocular and eyelid blepharitis is usually accompanied by swelling, conjunctivitis, pseudomembrane formation, and corneal and conjunctival epithelial defects [23]. A study conducted by Yip et al. [24] evaluated the outcome of 117 patients with SJS/TEN; 69% of patients had ocular lesions. A classification was made according to severity; mild ocular involvement occurred in 40% of patients, moderate in 25% and severe in 4%. 50% developed late complications, the most common of which were severe dry eye and ciliary disease [19, 24]. Although not widely reported, studies show acute gynaecologic involvement occurs in up to 77% of patients with SJS/TEN [25]. Changes include vaginal erosions and ulcers, painful urination or retention, discharge, pain and bleeding [26]. Gynaecologic consultation is needed to alleviate symptoms and prevent the development of sequelae that occur in 25% of women, which are vulvar adhesions and vaginal strictures that cause, among other things, dyspareunia and difficulty getting pregnant [25]. Often the lesions also affect the genitourinary system in men. The most common symptoms are penile erosions, followed by muscle involvement, leading to dysuria and haematuria in the acute phase. Long-term sequelae are relatively uncommon and can manifest as penile adhesions, urethral strictures, and stools [25]. Also, the psychosocial consequences of the disease, should not be underestimated [27]. The guidelines also address the prevention of recurrence and the treatment of chronic complications, which, as mortality from SJS/ TEN declines, are becoming more common [19]. Of great importance in a patient’s recovery are visits to a dermatology clinic for follow-up and treatment of skin complications, the most common of which are postinflammatory hyper-/ /hypopigmentation, photosensitivity, chronic pruritus, eruptive naevi, hypertrophic scarring, hair changes, like telogen effluvium, and nail changes [27]. If non-cutaneous complications occur, the patient should be referred by the coordinating physician, usually a dermatologist, to physicians of appropriate specialities. During routine follow-up, the recovering patient should be questioned about local symptoms, such as decreased visual acuity and shortness of breath, as well as generalized symptoms, including fatigue, weakness or depression, and a psychological evaluation should be considered in all patients [19, 20, 27]. In the authors’ experience, the ability to work with specialists from different disciplines is of considerable value in the treatment of TEN. As in the case of the first patient, involvement of the eyes and throat lesions, required cooperation with an ENT specialist and an ophthalmologist for successful treatment. With the second patient, his schizophrenia proved his hospitalization to be quite difficult as the patient was pulling out his venipunctures requiring constant consultations with an anaesthesiologist which enabled further measures to be taken to improve treatment. The patient was also consulted psychiatrically, and this examination made it possible to identify the drug potentially causing the TEN. The third patient who was suffering from cirrhosis, had a very acute course of TEN, and any treatment provided was ineffective. In order to comprehensively evaluate his condition, the patient was repeatedly consulted by internal medicine, anaesthesiology, cardiology specialists and for pain relief, with a palliative medicine physician.

The Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) scale is a model for estimating mortality. Risk factors considered are age ≥ 40 years, heart rate ≥ 120 beats per minute, presence of cancer or haematologic malignancy, initial % BSA of detached epidermis > 10%, blood urea nitrogen > 10 mmol/L, serum glucose > 14 mmol/L and serum bicarbonate < 20 mmol/L. A score of 1 point is given for each of the conditions met. The risk of death is, respectively, for scores 0–1 — 3.2%, 2 — 12.1%, 3 — 35.3%, 4 — 58.3%, and 5 or more > 90% [28]. SCORTEN is the best-known prognostic scale and a reliable parameter in predicting mortality in patients with SJS/TEN. Analyses of several case series have confirmed SCORTEN’s ability to accurately predict death [29]. However, there are papers indicating that the accuracy of this test may be limited [30]. The reliability not only of the predicted mortality risk but also of the component laboratory results and clinical features is subject to debate. There are calls to revise the score predicting death among TEN patients and to include new risk factors for death. With particular attention to the creation of more appropriate breakdowns by age and body surface area occupied, and the inclusion of more accurate renal function parameters [29, 30]. As shown in the analyses, recent studies show a much lower death rate than expected according to SCORTEN. With advances in the treatment of TEN, SCORTEN may overestimate mortality in centres with experience in treating this disease [22, 29]. In the case of the present patients, however, the SCORTEN scale was an effective predictive tool. Patients who scored 2, a predicted mortality of 12.1%, responded to treatment and survived. A patient whose condition was more severe and scored 4 on SCORTEN (predicted mortality of 58.3%) passed away.

Management of TEN relies on supportive care providing the conditions for re-epithelialization of the affected skin for which fluid resuscitation, pain management, wound care, and nutritional support are crucial [31]. The fluid resuscitation should maintain adequate tissue perfusion by achieving mean arterial blood pressure of 65 mmHg, central venous pressure in the range of 8 to 12 mmHg, and urine output in the range of 0.5 to 1 mL/kg/ hours [32]. A non-adhesive sterile dressing should be used to cover areas of skin erosion and care should be taken to prevent hypothermia, especially in the pre-hospital setting [33]. Nutritional support is critical in patients with TEN due to the hypercatabolic nature of the condition. Enteral nutrition is superior to parenteral nutrition given the reduced risk of bacterial translocation. A nasopharyngeal oropharyngeal examination may be used if the oral mucosa is significantly affected. Wound debridement of the affected area can be managed with a variety of options, including a biologic dressing (e.g., allograft, xenograft, and homograft), a biosynthetic dressing (e.g., biobrane), or a silver-impregnated dressing [31].

As for forms of systemic pharmacotherapy in TEN gluco­corticoid therapy is debatable. While some studies have shown a reduction in mortality when combined with IVIG therapy, other studies have shown conflicting results. The RegiSCAR study, published in 2008, showed a statistically significant increase in survival among those who received corticosteroid therapy, supporting the view that cortico­steroids may increase survival in patients with TEN [34]. The EuroSCAR study, which assessed the risk of using drugs in rare but severe cutaneous adverse reactions, including TEN, does not explicitly mention that corticosteroids decrease mortality, however, indicates that corticosteroid therapy does not increase mortality and may have a beneficial effect, however, this relation was not noticed among the present patients [8]. Cyclosporin has gained in importance in recent years. This medication inhibits the activity of T lymphocytes, which play a key role in the pathogenesis of TEN [35]. Successful treatment of SJS/TEN with cyclosporine was reported in a study of 44 patients, which showed a significant reduction in mortality as the standardized mortality ratio of SJS/TEN treated with cyclosporine was 0.42 [36]. An analysis by Harr et al. [37] showed that patients treated with cyclosporin had a significantly shorter time to complete re-epithelization, fewer patients with multiple organ failure were observed, mortality was reduced and clinical outcomes after the use of cyclosporin were improved. Nevertheless, these effects were not present in the present study patients. Clinical evidence regarding the effectiveness of IVIG in TEN is currently inconclusive as the results of systematic reviews and meta-analyses are conflicting. While some studies suggest a great potential benefit of IVIG, especially when combined with corticosteroids, others show no significant clinical benefit to its use. The potential mechanism of action for IVIG in the treatment of TEN relies on blocking the interaction between the Fas receptor and the Fas ligand, a reported pathway for keratinocyte death that is characteristic of TENs [38]. Some systematic reviews suggest that the current evidence does not generally support the clinical benefit of IVIG in the treatment of TEN, however, it should be noted that this analysis did not consider the potential impact of the different doses used of IVIG [39]. Another meta-analysis published in the Journal of the American Academy of Dermatology in 2020 showed that combined therapy with corticosteroids and IVIG significantly reduces the observed risk of death in patients with TEN [4]. This suggests that IVIG may play a beneficial role when used in conjunction with other treatments, however, the cost of IVIG is a major limiting factor. The use of IVIG in the treatment of TEN remains controversial and guidelines contain different recommendations. According to the European guidelines (S1) on the use of high doses of IVIG in dermatology, in the absence of alternative treatment methods based on scientific evidence, early administration of high doses of IVIG (≥ 2 g/kg) may be considered [40]. In the authors’ experience, IVIG is worth considering life-saving treatment in severe cases of TEN.

CONCLUSIONS

In summary, TEN also affects several internal organ systems in addition to the skin, including the eyes and mouth, respiratory, gastrointestinal/hepatic and genitourinary, which is why its treatment requires cooperation with specialists from different fields. Crucial in TEN management is potential causative drug withdrawal and topical treatment as well as early assessment with SCORTEN. Systemic steroid therapy could potentially reduce mortality, however, the evidence is lacking. Many support the role of immunoglobulins and cyclosporine in this condition management.

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Acknowledgements

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Author contributions

AW, PL, WW, NG — Data analysis and preparation of the manuscript; AW, LM-J, RC — Work plan and evaluation of the content.

Conflict of interest

The authors declare no conflicts of interest.

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Supplementary material

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