Granulomatous Hepatitis as a Consequence of Disseminated Mycobacterium bovis (M. bovis)

Abstract

A 77 year-old male with history of transitional bladder cell carcinoma diagnosed 12 years ago, presented for further evaluation of recurrent fever, night sweats and weight loss of 1-month duration. Previously he was treated with 3 transurethral tumor resections (TUR) over 7 years and 18 intravesicular Bacillus Calmette-Guerin (BCG) doses. His cancer recurred recently and he underwent a TUR 2 months prior to presentation followed by 2 intravesicular BCG doses, last dose 1 day prior to fever. An extensive infectious work up in the form of blood, urine, and radiographic evaluation was obtained and was negative. Blood and urine cultures were negative. He was empirically treated for BCG cystitis with an antimycobacterial (anti-TB) regimen consisting of isoniazid (INH), rifampin (R), ethambutol and vitamin B6 (B6). His fevers resolved on this regimen and he was discharged on this regimen. He was readmitted 10 days later with fevers. Repeat blood and urine cultures had no growth. In addition, he had mildly elevated transaminases, which were attributed to the R and was substituted with ciprofloxacin. With persistently elevated transaminases, a liver biopsy was done showing granulomatous hepatitis with non-necrotizing granulomas and negative acid-fast bacilli (AFB) stain. Due to BCG therapy, this histologic finding is most consistent with BCG-associated granulomatous hepatitis confirming the diagnosis of disseminated BCG. He was restarted on anti-TB therapy with INH, levofloxacin and B6. His fevers improved 5 days after initiation of therapy. He was discharged on these medications for a 6-month course. Surprisingly, 6 weeks later, initial blood and urine cultures grew M bovis. BCG is a live attenuated strain of M bovis. Intravesicular administration of BCG is commonly used as an adjuvant therapy in superficial bladder cancer. Disseminated BCG is a very rare complication following intravesicular BCG therapy. The prevalence of granulomatous hepatitis in disseminated BCG is 0.7%. Of patients with BCG-associated granulomatous hepatitis, only 10% of patients have tissue that test positive for AFB stains showing mycobacterial organisms. The mechanism by which BCG therapy can cause disseminated M bovis is not clearly understood. One thought is a Th1-mediated hypersensitivity reaction since a number of case reports demonstrated disseminated granulomas with negative AFB and no isolated organism. Our patient did have evidence of disseminated granulomas with negative AFB, but the organism was later isolated in his urine and blood, hence raising the hypothesis that the organism itself also can access the blood stream via uroepithelial cells and disseminate to other organs. In these cases, multi drug anti-TB therapy is recommended for three to six months with or without the addition of glucocorticoids.