Bacillus Calmette-Guérin (BCG) is an attenuated strain of the tuberculosis bacillus, Mycobacterium bovis. BCG induces an intense, localized inflammatory response upon instillation into the bladder. Its therapeutic mechanism of action is thought to involve the ingestion of viable mycobacteria by urothelial cells, which triggers a cytokine-mediated inflammatory response that results in the destruction of tumor cells.
Since its introduction in the 1970s, intravesical BCG treatment has been an effective treatment option of superficial bladder cancer, with a favorable safety profile and typically localized and self-limited side effect . However, systemic complications can occur. They include granulomatous involvement of lung (pneumonititis), liver (hepatitis), and bone marrow . Ophthalmologic and vascular complications have also been described but are considered extremely rare.
According to our literature review, the combination of granulomatous hepatitis, pneumonitis, choroiditis and aorto-enteric fistulization due to disseminated Mycobacterium bovis infection has not previously been reported. Our patient was initially referred for a hepatologic evaluation. His liver biopsy demonstrated the typical features of granulomatous hepatitis with numerous epitheloid noncaseating granulomas with intralobar distribution. Despite the negative acid fast stain, a high level of suspicion for mycobacterial infection resulted in further testing and the eventual establishment of multiorgan involvement with Mycobacterium bovis BCG. While hepatic, bone marrow, and pulmonary involvement have been extensively documented, the occurrence of mycobacterial choroiditis has only been reported in one prior case report . In this study, a 57 year-old patient developed bilateral ocular lesions that resembled those observed in our patient, following a 6-month course with intravesical BCG with the Connaught strain. Similar to our patient, his choroidal lesions did not progress after therapy with rifampin, isoniazid, and ethambutol .
Similarly, the development of an aortoenteric fistula due to disseminated BCG infection is a rare occurrence, with less than 20 cases documented in the literature . The proposed mechanisms of fistulization include hematogenous route via the vasa vasorum or local extension and lymphatic spread [7, 9].
Our case highlights the importance of considering unusual complications of BCG therapy and of appropriately monitoring patients at risk.
The proposed mechanisms of liver damage by BCG include direct infection as well as hypersensitivity reactions . In 1996, Leebeek demonstrated the presence of Mycobacterium bovis in liver tissues by PCR amplification . This finding supported the concept of hematogenous dissemination and direct tissue damage to the liver [11, 12]. However, the beneficial effect of adding corticosteroids to the antituberculous agents and the striking eosinophilic infiltration of the liver suggest that hypersensitivity reactions may also play a role [12, 13].. The absence of necrosis in the granulomas has been interpreted as additional evidence of a hypersensitivity reaction. However, hepatic granuloma may resemble those seen in miliary tuberculosis, in which necrosis is usually absent, rather than the caseating lesions of primary tuberculosis with liver involvement. With respect to establishing a diagnosis, our case highlights the limitations of AFB staining and conventional mycobacterial culture. Acid-fast stains are positive in only 10 percent of cases with hepatic involvement, possible due to the fact that a minimum of 10,000 organisms per gram of tissue are necessary to result in a positive stain . Mycobacterial cultures for the detection of BCG lack sensitivity and require a minimum of six to eight weeks of incubation. Molecular assays, including PCR-based tests, have superior sensitivity. However, even they may fail due to the paucity of organisms .
With respect to treatment, the recommended first line therapy for severe systemic BCG infection is the administration of isoniazid, rifampin and ethambutol. Treatment with pyrazinamide is not recommended since all known strains of Mycobacterium bovis are pyrazinamide-resistant . Adjunctive therapy with corticosteroids has been advocated by some authors. This recommendation is based on data from animal models and anecdotal clinical reports suggesting that corticosteroids improve the histological outcomes and treatment responses. However, corticosteroid should not be given without concomitant antimycobacterial coverage since they might increase the risk of systemic infection. With respect to prophylactic anti-mycobacterial treatment, the concomitant administration of BCG and antitubercular drugs has been advocated. However, this approach may result in drug-induced hepatitis and reduce the antitumor effects of BCG. Futhermore, systemic BCG infections can occur despite antibiotic prophylaxis.
In summary, we present an unusual case of multi-organ involvement with systemic mycobacterial infection following intravesical BCG treatment of bladder cancer in an immunocompetent patient. The constellation of granulomatous hepatitis, choroiditis and aortoduodenal fistula with gastrointestinal hemorrhage has not been previously reported . Our patient's course highlights the importance of recognizing potential risks from BCG treatment - even months after completion of treatment and in the absence of a history of immunodeficiencies - and of addressing its wide range of end-organ complications.