Granulomatous Hepatitis after BCG Intravesical Immunotherapy

Abstract

Purpose: An 80 y/o male presented with a progressively worsening fever, chills and night sweats 10 days after he received his fifth intravesical BCG instillation for his low-grade bladder carcinoma. Review of systems was remarkable only for mild dysuria and hematuria. Physical examination revealed a temperature of 102°F. He had no hepatosplenomegaly or lymphadenopathy. Labs were significant for leukopenia (3000/μL) and elevated LFTs (alkaline phosphatase [ALP]-378, AST-70, ALT-26 U/L). Prior to presentation, Isoniazid was initiated by his urologist for presumptive BCG infection. Rifampin and levofloxacin were added upon admission to the hospital. Routine blood and urine cultures did not yield any pathogens and serology for viral, bacterial, and fungal infections were negative. Chest x-ray was unremarkable but a chest-CT showed diffuse nodular infiltrates suspicious for Mycobacterium infection. An USG-guided liver biopsy was performed for a persistently elevated ALP, and revealed granulomatous hepatitis with non-caseating epitheloid granulomas and lymphocytic cholangitis. Gram, AFB, GMS, FITE and immunohistochemical stains did not detect any organisms, and tissue culture was negative. Worsening pancytopenia prompted a bone marrow biopsy that revealed several large granulomas. The patient gradually improved, and his fever subsided within several days of anti-tuberculous therapy. Liver abnormalities resolved during the following week. He completed a 6-month course of isoniazid and rifampin, and had no complications at 1-year follow-up. Intravesical BCG is an effective treatment for superficial bladder cancer (success rate: 63-100%). Minor complications including hematuria, cystitis, fever (<38.5°C) and malaise are quite common, whereas major complications such as both local (granulomatous prostatitis, epididymo-orchitis) and systemic reactions (fever >39.5°C, sepsis, cytopenias, granulomatous hepatitis and pneumonitis) occur occasionally. Granulomatous hepatitis is a rare (<0.4%) and serious complication after BCG instillation, with unclear pathogenesis. It has been considered a hypersensitivity reaction to BCG, but cases have been reported in which mycobacteria were seen on staining and mycobacterial DNA was detected in liver tissue suggesting a liver infection after haematogenous dissemination of BCG, rather than hypersensitivity. There have been no prospective studies to evaluate the optimal treatment for BCG infection. In severe systemic cases, some data supports the administration of three anti-tuberculous drugs including isoniazid, rifampin and ethambutol for at least 6 months. The addition of corticosteroids during initial therapy may assist in a faster resolution of inflammatory complications.