INTRODUCTION

Toxicoderma is a skin and mucous membrane lesion resulting from the administration of drugs [1]. In certain situations, they may be responsible for multivisceral failure, i.e., hepatic, renal, or cardiac failure, that may be life-threatening, with a mortality rate reaching 30% of cases [2]. Herein, we report the case of a young woman admitted to our department for the management of Lyell’s syndrome responsible for severe liver failure.

CASE REPORT

A nineteen-year-old female patient with no medical history was admitted to the emergency department of IBN SINA University Hospital to manage severe toxicoderma. Fifteen days before admission, she took a rat poison based on an anticoagulant with suicidal intent. The patient was hospitalized in the intensive care unit of a private structure for 24 hours, then she was discharged after seeing a psychiatrist, who prescribed her a serotonin and norepinephrine reuptake inhibitor, lamotrigine, and an anxiolytic. These two last drugs were stopped ten days later following the appearance of a macular rash on the face that rapidly spread to the rest of the body and was replaced by benzodiazepine. Given the lack of improvement in her clinical condition, the patient presented to the emergency room two days later. On admission, she was febrile at 39° C, with facial edema without signs of upper airway compression, and edema of the lower limb taking the bucket. Dermatologically, she had a painful maculopapular rash, purpuric in places, affecting more than 90% of the skin surface, without bullous detachment (Figs. 1a – 1c), affecting the genital mucosa as well, with yellowish genital secretions, all associated with erosive cheilitis, and purulent ocular conjunctival secretions. Her laboratory work-up revealed major hepatic failure, with AST at 3412 IU/L, ALT at 4153 IU/L, a low prothrombin level of 17%, and a collapsed factor V activity at 29%. She also presented hyperbilirubinemia at 37 mg/L, predominantly conjugated, without biliary tract dilatation on abdominal ultrasound, and a normal liver morphology. Our therapeutic approach consisted of the withdrawal of all hepatotoxic treatment, the introduction of N acetylcysteine with a loading dose of 15o mg/kg over one hour followed by a maintenance dose of 50 mg/kg/4 h, vitamin K supplementation, management of fever with physical means, rehydration with a saline serum, and topical care for the skin and mucous membrane lesions. A declaration to the pharmacovigilance center was made. Liver serologies returned negative. The evolution was marked by a skin detachment on the trunk with several erosive areas, involving 35% of the skin surface, with a negative Nikolsky sign. The skin biopsy returned in favor of toxic epidermal necrolysis, and the direct immunofluorescence test was negative. The patient was later transferred to the dermatology department after improving the hepatic function and correcting the hydric deficit. She was discharged after ten days with improvement in her skin lesions and referred to the psychiatric unit.

Figures 1: (a-c) Maculopapular rash with purpuric areas on the patient’s skin.

DISCUSSION

Lyell’s syndrome, or toxic epidermal necrolysis, is a serious drug-induced skin and mucous membrane disorder with a potentially deadly course. However, this medical condition affects only 1 to 3 persons per million inhabitants per year [3]. Stevens–Johnson syndrome and Lyell’s syndrome represent two different states of severity of the same affection. Toxic epidermal necrolysis is defined by a detached skin surface greater than 30% of the total body surface, while Stevens–Johnson syndrome is characterized by a detached surface of less than 10%, and the transition between the two is represented by the overlap syndrome [4].

To date, the pathophysiological mechanisms remain partially elucidated. They are based on an immunological process involving delayed hypersensitivity [5]. The first phase takes 7 to 10 days and involves sensitization. The drug is recognized by the immune system as an antigen, leading to the activation of specific CD4+ and CD8+ T lymphocytes. The second phase is triggered by re-exposure to the drug. These specific T lymphocytes diffuse into all tissues, particularly the skin, and induce keratinocyte apoptosis either via cytotoxic proteins, membrane expression of the FasL molecule, or tumor necrosis factor production [5].

This hypersensitivity reaction is commonly secondary to medication exposure, so the investigation should include all drugs taken during the eight weeks preceding the episode [5]. However, certain rare forms were linked to infectious causes [6]. The EuroSCAR study identified the most common drugs related to this medical condition: sulfonamides, allopurinol, carbamazepine, penicillins, barbiturates, lamotrigine, and phenytoin [7]. Other antibiotic classes (macrolides, quinolones, cephalosporins, tetracyclines), pantoprazole, and tramadol were associated with a significant yet lower risk. In our patient’s case, lamotrigine was found to be the main causative factor. Other risk factors were identified, such as genetic predisposition. For instance, allopurinol toxic epidermal necrolysis in Hans Chinese, Thai, and Malaysians is associated in 100% of cases with the presence of HLA-B*5801 [8]. In addition, HIV-infected patients appear to be at much greater risk of developing toxic epidermal necrolysis [5], and this is explained by their immune dysfunction and frequent exposure to risky drugs.

Skin symptoms are often preceded by a flu-like prodrome with an impairment of physical condition and fever [5]. A confluent erythematous macule then appears. It begins on the trunk and spreads out from there. These skin lesions then transform into large blisters. Erosive damage to mucous membranes is frequent and synonymous with severity: all mucosal surfaces may be affected: oral, genital, ocular, anal, tracheobronchial, and digestive [5]. Systemic involvement is common in toxic epidermal necrolysis and is linked to a process of epithelial destruction similar to that affecting the skin. Respiratory symptoms may be minor when the lesion is limited to the tracheobronchial epithelium, yet sometimes it may lead to acute respiratory distress syndrome, which is a major mortality factor. The involvement of the digestive tract is also frequent [9]. Fifty percent of patients will present a significant rise in serum transaminases (two to three times normal), yet acute hepatitis is present in only 10% of cases [10], and it worsens prognosis and increases the mortality rate. It may be related to various factors, such as drug-related factors, septicemia, or low cardiac output secondary to profound hypovolemia. As for renal function disorders, most often, they are secondary to hypovolemia, and only very few cases of glomerulonephritis have been reported [9]. Hematological damage is present in almost all cases. The main manifestations are anemia, neutropenia, and lymphopenia due to selective and transient depletion of CD4+ T helper lymphocytes. Thrombocytopenia and hypereosinophilia are less frequent [4].

Therapeutic care must be provided earlier in a specialized burns unit [5]. First of all, it is imperative to stop using any drug that may have been involved and to notify the pharmacovigilance center. Nevertheless, skin lesions may sometimes continue to appear for up to four weeks after treatment has been stopped, depending on its half-life [5]. In the acute phase, the management of the hemodynamic state is crucial with a compensation of the hydric deficit proportional to the surface area detached, taking into account that volemic needs are usually lower in toxic epidermal necrolysis [9]. Moreover, an electric air mattress is essential to prevent heat loss, as well as nutritional support with a high-protein, high-calorie diet, and pain management with morphine titration. The management of mucocutaneous lesions varies depending on the center: some recommend debridement, others recommend leaving the necrotic epidermis in place to act as a natural dressing [5]. Therefore, local care is crucial in preventing infectious complications and mucosal sequelae, particularly, ophthalmological and genital. To date, no specific treatment is superior to supportive care alone [4]. Several molecules have been tested, notably high-dose corticosteroids and more recently IV immunoglobulins, yet no study has proven their efficiency.

CONCLUSION

Toxic epidermal necrolysis is a rare condition with a high morbidity/mortality rate, which may be responsible for severe organ failure, requiring supportive care in the intensive care unit. Symptomatic treatment is becoming well-codified and has helped reduce the mortality rate. To date, no specific treatment has yet proved to be effective. So, our only means of prevention is to sensitize doctors to the risks of unjustified drug prescriptions and to systematically consult them early in the event of any post-drug symptoms.

REFERENCES

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