Ibuprofen-induced extensive toxic epidermal necrolysis - a multidisciplinary therapeutic approach in a single case.

Abstract

Dear Sir, Toxic epidermal necrolysis (TEN) or Lyell’s syndrome is a life-threatening (up to 90% mortality rate), extensive cutaneous, drug-induced adverse event1. Similar skin damage/defects -but usually without a fatal outcome- are observed following drug administration in Stevens-Johnson’s syndrome (SJS; milder form) and TEN/SJS (intermediate type). In these conditions the epidermis can be detached from the underlying structures (dermis) over the whole body surface. Mucous membranes may also be affected. The precise aetiopathogenesis of TEN is still unclear. Some toxic metabolites, inflammatory mediators or modifiers, as well as cytotoxic T lymphocytes, regulatory T cells and dermal dendrocytes could induce apoptosis or necrosis of epithelial cells1–3. The human leucocyte antigen (HLA) system also plays an important role in the pathogenesis of TEN, since some drugs may bind directly to the HLA-complex and create self-reactivity due to the drug-modified HLA-peptide repertoire. This event is mediated by cytotoxic T lymphocytes and/ or natural killer cells after their interaction with cells expressing the HLA-complex3. We report here the case of a 21-year old female with extensive erythema, necrosis, and exfoliating bullous detachment of the epidermis and mucous membranes (conjunctival, oral and genital; affected skin area=80%; Figure 1A and 1B). Initially, she had an influenza-like prodrome after taking ibuprofen to treat a headache and dysmenorrhea. She was admitted to the Clinic for Plastic Surgery of MMA (Belgrade, Serbia) and on presentation she was febrile (39.3 °C) with a characteristic positive Nikolsky’s sign. Laboratory analyses were as follows: haemoglobin, 121 g/L; white blood cell count, 6.77×109/L (neutrophils 80%, lymphocytes 25%, eosinophils 4%, monocytes 1%), platelet count, 466×109/L; elevated levels of C-reactive protein, aspartate aminotransferase and alanine aminotransferase (330 mg/L, 80 IU/L and 145 IU/L, respectively), and low concentrations of total proteins (50 g/L) and albumin (22 g/L). The results of coagulation studies and tests for viral infections were normal. Skin biopsy demonstrated prominent cell death with basal vacuolar changes and lymphocyte infiltrates, obscuring the dermo-epidermal junction (Figure 1C), which confirmed the clinical diagnosis of TEN. Figure 1 A) and B) Female patient with TEN: extensive erythema, necrosis, and critical muco-cutaneous lesions with intense exfoliation. C) Cell destruction with lymphocyte infiltrates and distraction of the dermo-epidermal junction. D) Therapeutic apheresis - ... The first-line treatment was immediate withdrawal of theculprit drug, elimination of the drug and its metabolites, and fluid resuscitation with crystalloid infusions (1 mL/kg of body weight per hour) via a central venous catheter, adjusted on the bases of the arterial blood pressure (>65 mmHg), central venous pressure (≤10 mmHg) and urine output (diuresis rate). The patient was isolated (using aseptic techniques and state) and local dermatological and ocular topical treatment were applied continuously. Nutrition was provided enterally via a nasogastric tube. In the early treatment of this patient, we performed our originally designed multimodal therapeutic apheresis -plasma exchange (PE) combined with leucapheresis- using COBE®-Spectra apheresis-sets (Terumo BCT, Lakewood, CO, USA) and a sterile connected multibag system. Multimodal therapeutic apheresis simultaneously provides rapid improvements in more than one blood abnormality and aids the patient’s recovery from a live-threatening emergency to a clinical condition with a potentially positive outcome4,5. The rationale for initial plasma exchange in this case was to eliminate/decrease the level of residual ibuprofen and its metabolites, critical cytokines (such as tumour necrosis factor-α, interferon-γ), and drug-induced inflammatory mediators (perforin, granzyme B released from cytotoxic T lymphocytes and granulysin secreted by cytotoxic T lymphocytes and natural killer cells) from the circulation (urgent plasma depuration). Plasma exchange was performed on three consecutive days by processing an average of 5900±952 mL of the patient’s whole blood. A total of 5.4-fold the plasma volume was exchanged and replaced by albumin in normal saline (Figure 1D). The basic goal of the leucapheresis-treatment was to reduce the circulating lymphocyte count in the patient’s blood to obtain an immunomodulatory effect. The patient’s subsequent systemic treatment included broad-spectrum antibiotics (chosen on the basis of the skin microbial findings), intravenous immunoglobulins (dose 1.0 g/kg of body weight per day for 3 consecutive days; infused over 6 hours) and corticosteroids (dose 0.5 mg/kg of body weight)1,2. This young female patient recovered completely after 1 month of intensive systemic and topical treatment. In conclusion, this multidisciplinary management -fluid resuscitation, urgent plasma depuration and immunomodulation (multimodal therapeutic apheresis), as well as topical and systemic medications (antibiotics, intravenous immunoglobulins and corticosteroids)- undoubtedly prevented septicaemia and multisystem organ failure, the major cause of death in severe TEN.