A thin line: generalized bullous fixed drug eruption for Stevens-Johnson syndrome/toxic epidermal necrolysis?

Dear Editor, A 49-year-old male presented to our outpatient department with complaints of diffuse redness and pain over the skin with multiple fluid-filled lesions and erosions of 2 days’ duration. The patient was apparently asymptomatic till 4 days back when he developed fever, diarrhea associated with abdominal pain for which he was started on tablet ciprofloxacin and tinidazole. Within 6 h of intake of the drug, he complained of diffuse darkening of skin associated with pain and tenderness over the trunk and extremities. Over the course of the next day, he developed fluid-filled lesions interspersed over a background of generalized redness and darkening of skin. These painful blisters were flaccid and ruptured easily on minimal manipulation, leading to erosions. He also complained of soreness in the tongue and a burning sensation in the mouth, impairing oral intake of meals, and pain and also complained of a burning sensation on passing urine and inability to retract foreskin over the glans. There was no history of similar lesions or dusky-red raised or purplish lesions at the time of onset or in the past. There was no fever with chills, lethargy, malaise, swelling of limbs, breathlessness, decreased urine output, redness, or discharge from the eyes. His general condition was fair (not sick looking/toxic). There was tachycardia (114 beats per minute) but no fever or tachypnoea. Systemic examination was unremarkable. Dermatological examination revealed generalized involvement of the entire body, sparing the face, scalp, distal third of the forearm and hands, legs, palms, and soles in the form of diffuse hyperpigmentation with tenderness. There were multiple, polysized, discrete to coalescent flaccid vesicles, and bullae leading to erosions covering up to 35% of total body surface area (Fig. 1a–c). Nikolsky’s sign was positive. There was also involvement of the oral mucosa in the form of erythema, glossitis, and angular cheilitis with a few erosions on the hard palate and labial mucosa. There was erythema, edema, and erosions over the prepuce, causing difficulty retracting it. Hemorrhagic crusting of the lips characteristic of toxic epidermal necrolysis (TEN) was conspicuously absent (Fig. 1d). Nor were the nasal mucosa/eyes involved. Skin biopsy for histopathology revealed a subepidermal split with dense inflammatory infiltrate in the superficial dermis. Necrotic keratinocytes were scattered in the basal as well as spinous layer of epidermis (Fig. 2a, b). Based on the sudden onset of skin lesions within few hours of intake of the culprit drug (ciprofloxacin, tinidazole), nontoxic look of the patient with no fever, and absence of characteristic hemorrhagic crusting of lips and absence of full-thickness necrosis of epidermis in histopathology, a diagnosis of generalized bullous fixed drug eruption (GBFDE) was favored over Stevens-Johnson syndrome (SJS)/TEN. He was started on tablet prednisolone at 1 mg/kg body weight per day, to which he responded well, and the lesions healed rapidly over the course of a week (Fig. 3a–d).Figure 1: (a–c) Generalized erythema and hyperpigmentation with tenderness and flaccid bullae leading to erosions covering up to 35% of the total body surface area. (d) The image shows erythema of the oral mucosa, glossitis, and angular cheilitis. There was no hemorrhagic crusting of the lips.Figure 2: (a, b) Skin biopsy for histopathology shows a subepidermal split with dense inflammatory infiltrate in the superficial dermis. Necrotic keratinocytes are scattered across the basal as well as the spinous layer of epidermis (H&E, ×20, ×40).Figure 3: (a–d) Posttreatment images after 7 days of oral prednisolone at 1 mg/kg body weight per day, resulting in desquamation with re-epithelialization.GBFDE is often mistaken for SJS and TEN due to its diffuse bullous presentation [1]. However, several key points aid differentiation. GBFDE is mostly triggered by NSAIDs and antimicrobials (sulfonamides, fluoroquinolones, and tinidazole/metronidazole), whereas SJS-TEN is mostly caused by anti-epileptics, sulfonamides, nevirapine, and allopurinol [2]. GBFDE lesions appear within hours of drug re-exposure, whereas SJS/TEN develops days to weeks after drug initiation [3]. Mucosal (oral, nasal, eyes, and genital) involvement in SJS-TEN is severe with characteristic hemorrhagic crusting of the lips, but is comparatively milder in GBFDE. SJS-TEN is often accompanied by purpuric dusky macules (TEN with spots) but is absent in GBFDE [4]. Skin pain and tenderness are significantly greater in SJS-TEN, often requiring opioid analgesics, whereas pain in GBFDE is relatively less [3]. The incidence of systemic complications secondary to acute skin failure is rare in GBFDE, whereas they significantly contribute to mortality in SJS-TEN [5]. The time taken for epidermal regeneration is rapid (a week) in GBFDE but, on average of 3 weeks in SJS/TEN [6]. Histopathology of SJS-TEN shows full-thickness necrosis of the epidermis, basal vacuolar degeneration, and extensive dermal lymphocytic infiltration. In GBFDE, the necrosis of keratinocytes is patchy with relatively mild inflammation in the dermis. Serum granulysin level-a marker for SJS/TE is significantly elevated in SJS/TEN but is normal or mildly increased in GBFDE and may serve as a potential tie-breaker in times of confusion [6]. Recognizing these differences is crucial to differentiate between these two entities for appropriate management. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given consent for images and other clinical information to be reported in the journal. The patient understands that names and initials will not be published and that due efforts will be made to conceal the patient’s identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. “Data availability statement”: Data is available upon request.