A 42-year-old male with a reported history of resolved hepatitis C was admitted to hospital due to fever and sore throat for 9 days, combined with a generalized rash over the entire body for 5 days.
The patient had not taken new medications in the recent 2 months until 8 days prior to this admission, when the patient visited a local clinic for flu-like symptoms of fever, sore throat, and general malaise combined with muscle weakness and was prescribed non-steroidal anti-inflammatory drugs (NSAIDs):mefenamic acid and diclofenac:for 3 days with acetaminophen and famotidine. However, the fever persisted despite the treatment, with subsequent development of itchy erythematous macules and papules spreading from the face and trunk to the extremities 5 days prior to this admission. Associated symptoms of ophthalmalgia, conjunctival injection, and lip swelling were also noted. After revisiting the local clinic and obtaining an additional prescription for ibuprofen, he visited the emergency department of another hospital 4 days prior to this admission, where numerous confluent erythematous to purpuric macules and patches on the face, trunk, and extremities, with variously sized erosions arising from the erythematous base were seen. The diagnosis of SJS was thus confirmed. The patient was then transferred to our hospital for further treatment.
On admission to our hospital, the patient was clear and oriented, with stable vital signs. Physical examinations showed that generalized confluent erythematous to purpuric macules and patches were distributed on the face, trunk, and limbs, with some flat erythematous spots present on the distal extremities. A sum of erythema of 35% total body surface area (TBSA) with blistering of 8% TBSA was calculated after the RegiSCAR review. Mucosal involvement with the presence of conjunctival and oral ulcers were also noted (Figure 1). Viral panel, mycoplasma pneumoniae infection and autoimmune survey yielded negative results (Supplementary Tables S1, S2).The skin lesions gradually improved to brownish and scaly characteristics, with near resolution noted at around day 14 under treatment with systemic corticosteroids (intravenous methylprednisolone), equivalent to 1.2-2.6 mg/kg of prednisone per day, combined with topical antibiotic ointments. Further laboratory examination revealed progressively elevating liver function enzymes and jaundice on day 6 of hospitalization (AST/ALT: 581/1488 U/L; ALP/GGT: 667/1990 U/L; T-Bil/D-Bil: 19.81/15.35 mg/dl) (Figure 2). Elevated IgG, C3, and C4 levels were also noted, without evidence of viral hepatitis. A liver biopsy was thus performed on day 6, and showed cholestatic hepatitis with marked perivenular cholestasis, ballooning of hepatocytes, and Councilman bodies with microgranulomas. Aggregation of histiocytes, neutrophils, and eosinophils were seen in the hepatic lobules. In a total of 10 portal tracts, only three bile ducts survived, which showed degeneration and cell senescence changes (i.e., increased nuclear to cytoplasm ratio, uneven nuclear spacing, drop-out, and syncytia formation; Figures 3A,B). VBDS was thus diagnosed. Due to progression of cholestasis and hepatitis on day 12 (AST/ALT: 973/2455 U/L; ALP/GGT: 815/3165 U/L; T-Bil/D-Bil: 34.91/22.81 mg/dl), systemic corticosteroids were up-titrated to the equivalent of 2.6 mg/kg of prednisone per day, with the capsule form of mycophenolate mofetil initiated at 250 mg twice a day and later up-titrated to 750 mg twice a day. Evaluation for possible liver transplantation was arranged after discussion with the patient and family.
The patient completed pre-transplantation evaluation uneventfully. A significant decrease in liver enzymes and bilirubin levels was observed on day 28 (AST/ALT: 184/647 U/L; GGT: 1,131 U/L; T-Bil/D-Bil: 25.58/15.18 mg/dl). The patient showed resolution of SJS with scars remaining on his extremities and denied discomfort. However, the patient showed a gradual decrease in the hemoglobin level to 8.7 g/dl on day 34, with subsequent discovery of cytomegalovirus (CMV) infection via colonoscopy biopsy and blood tests (a CMV viral load of 1,040,000 cp/ml was detected on day 42). Ganciclovir was thus initiated for treatment. Due to the presence of nucleated red blood cells in peripheral blood and the pathological finding of sinus histiocytosis with hemophagocytosis in specimens of the small intestine, a bone marrow study was conducted on day 58. The result showed hemophagocytosis in bone marrow, which met the HLH diagnostic criteria. Intravenous immunoglobulin was thus given from day 61 to day 64.
A repeat liver biopsy was performed on day 127, which revealed intrahepatic cholestasis with marked perivenular bile stasis. Eight portal tracts were observed with seven bile ducts, with six showing degeneration and cell senescence changes. An increase in the bile duct ratio was seen compared to that of the previous study (Figure 3C). Despite the resolution of SJS and VBDS, the patient still developed hypovolemic shock combined with septic shock episodes and died on day 236.