A case report published in the African Journal of Urology describes the severe and potentially fatal complications arising from intrarenal instillation of Bacillus Calmette-Guerin, or BCG, in a patient with upper urinary tract carcinoma in situ. The study details the clinical course of a 68-year-old woman who developed gram-negative sepsis and granulomatous cholestatic hepatitis following the first of her planned BCG treatments. This rare but serious outcome highlights the diagnostic and therapeutic challenges clinicians face when managing systemic BCG infections, particularly when they present with concurrent bacterial sepsis that can obscure the underlying mycobacterial etiology.
BCG immunotherapy is the most widely used treatment for non-muscle invasive urothelial carcinomas, including carcinoma in situ of the bladder and upper urinary tract. While generally well-tolerated, the therapy carries a risk of serious systemic complications. In this specific case, the patient had previously undergone a radical cystectomy for muscle-invasive bladder cancer, during which bilateral carcinoma in situ was found in the distal ureteral margins. Because adequate ureteral length for further resection was unavailable, the medical team opted for a kidney-sparing approach involving ureterocutaneostomy and adjuvant intrarenal BCG instillations.
The first BCG instillation was administered via a retrograde gravity-drip technique through a preexisting left single-J stent. The procedure was intended to last one hour but was discontinued after 20 minutes when the patient experienced rigors and rapidly developed sepsis. Despite initial stabilization with dual antibiotic therapy consisting of meropenem and vancomycin, as well as fluid resuscitation, the patient remained vasopressor-dependent for two days. Laboratory results showed marked leukocytosis and elevated inflammatory markers, while blood and urine cultures isolated Klebsiella oxytoca, indicating a concurrent gram-negative bacterial infection.
Although the patient initially improved and the isolated bacteria were susceptible to the prescribed antibiotics, her condition deteriorated again as she remained febrile and liver transaminases began to rise. Control blood cultures were sterile, suggesting that the persistent fever and organ dysfunction were not solely due to the bacterial sepsis. Given the recent BCG exposure, the clinical team suspected a systemic BCG infection and initiated anti-tuberculosis therapy with adjunctive prednisone on the 12th day of hospitalization.
By the 15th day of treatment, the patient developed jaundice and severe illness, with laboratory results revealing a cholestatic pattern of liver injury. Total bilirubin levels reached 131 µmol/L, and alkaline phosphatase was significantly elevated at 430 U/L. A multislice computed tomography scan of the abdomen showed gallbladder wall thickening, cholangitis, and enlarged, partly necrotic periportal lymph nodes, but no signs of biliary obstruction or focal liver lesions. These findings pointed toward an inflammatory rather than obstructive cause for the hepatic dysfunction.
To clarify the nature of the liver injury, a liver biopsy was performed on the 20th day. The histological analysis revealed numerous non-caseating granulomas composed of epithelioid cells, rare multinuclear giant cells, and lymphocytes, primarily located within the liver lobules. The portal areas were edematous and densely packed with mononuclear cells, with piecemeal necrosis present in half of the affected area. Acid-fast staining and molecular PCR assays failed to detect Mycobacterium bovis, a common occurrence in BCG-related hepatitis where the host’s immune response rapidly controls bacillary replication, rendering live organisms difficult to detect.
The patient’s condition continued to worsen until the 22nd day, when she developed acute liver failure with impaired synthetic function and signs of portal encephalopathy. Her Model for End-Stage Liver Disease score reached 19, and she subsequently developed acute respiratory failure due to an extensive right pleural effusion. At this stage, the patient was also found to be positive for SARS-CoV-2, which may have contributed to the respiratory compromise. The initial anti-tuberculosis regimen included isoniazid, rifampicin, and ethambutol, but isoniazid was replaced with moxifloxacin due to lack of clinical improvement and potential hepatotoxicity.
Adjunctive systemic corticosteroids, specifically prednisone, were administered to manage the hypersensitivity reaction driving the inflammation. The rationale for this approach is that the symptoms of disseminated BCG infection are largely the result of the sensitized host’s immune response to the bacilli. From the 23rd day onwards, the progression of liver and respiratory failure halted, and a slow recovery began. The prednisone was gradually tapered over six weeks, and the patient was discharged after 43 days in the hospital with satisfactory liver function and respiratory status.
The case underscores the importance of early recognition and timely treatment of systemic BCG complications. The delay in initiating anti-tuberculosis and corticosteroid therapy, partly due to the confounding presence of gram-negative sepsis, resulted in a period of severe illness with a poor prognosis according to the Sequential Organ Failure Assessment score. The authors note that earlier intervention could have led to faster recovery and better survival chances. The successful outcome in this case supports the use of anti-tuberculosis drugs, excluding pyrazinamide due to intrinsic resistance of M. bovis, combined with corticosteroids for severe BCG-related hepatitis.
Diagnostic confirmation of BCG infection remains challenging, with microbiologically positive diagnoses achieved in only a minority of cases. The presumptive diagnosis in this patient was based on the short interval between BCG instillation and disease onset, the characteristic histological finding of non-caseating granulomas, the exclusion of other causes of granulomatous hepatitis, and the therapeutic success with anti-tuberculosis and corticosteroid therapy. This case adds to the limited body of evidence regarding intrarenal BCG complications, which are thought to have similar rates to those following intravesical administration, though systematic data are lacking.
The study emphasizes that while BCG is an effective treatment for upper urinary tract carcinoma in situ in patients with imperative conditions, it must be administered with extreme care to minimize the risk of systemic dissemination. The timely initiation of appropriate anti-tuberculosis and immunosuppressive therapy is paramount for achieving favorable outcomes in these rare but life-threatening scenarios.
Follow-up over the first six months showed no signs of relapse, and urine cytology remained negative for high-grade urothelial carcinoma. The patient completed a six-month course of anti-tuberculosis treatment with moxifloxacin and rifampicin, with ethambutol added for the first two months. This case report serves as a critical reminder of the potential severity of BCG-related complications and the necessity for a high index of suspicion in patients undergoing intrarenal immunotherapy.
Carcinoma in situ represents an aggressive, high-grade urothelial malignancy that carries up to a 54 percent probability of progressing to muscle-invasive disease within five years if left unmanaged. Unlike exophytic papillary tumors classified as Ta or T1, carcinoma in situ manifests as flat and frequently multifocal mucosal lesions that typically elude visual detection during routine cystoscopy or ureteroscopy. Because simple endoscopic resection cannot reliably eliminate such widespread microscopic disease, endoluminal therapy serves as the primary bladder-sparing strategy. For bladder carcinoma in situ, standard bacillus Calmette-Guérin protocols involve an induction course administered once weekly for six weeks, followed by periodic three-week maintenance cycles given at three, six, twelve, eighteen, twenty-four, thirty, and thirty-six months. In bladder disease, this regimen produces complete response rates exceeding 80 percent, with approximately 66 percent of complete responders remaining recurrence-free at five years and nearly 80 percent achieving overall five-year progression-free survival.
When applied to upper urinary tract carcinoma in situ, intrarenal bacillus Calmette-Guérin instillation demonstrates therapeutic outcomes comparable to intravesical treatment. Pooled findings across 182 upper tract patients revealed complete response, recurrence-free survival, and progression-free survival rates of 84 percent, 66 percent, and 84 percent, respectively, over a median follow-up of 3.5 years. Despite these favorable efficacy figures, radical nephroureterectomy remains the conventional gold standard because accurate upper tract staging, local delivery, and surveillance present persistent technical obstacles. Consequently, organ-sparing intrarenal instillations are restricted to imperative clinical circumstances, including solitary kidneys, bilateral lesions, severe baseline chronic kidney disease, or major surgical comorbidities. Delivering the mycobacterial suspension into the renal pelvis entails distinct mechanical risks, notably the lack of an anatomical reservoir to retain the fluid and the hazard of pyelovenous influx, which can facilitate systemic intravascular dissemination if intrapelvic pressure rises during retrograde single-J catheterization or antegrade percutaneous nephrostomy.
Broader clinical registries illustrate both the relative rarity and the severity of systemic complications following bacillus Calmette-Guérin instillation. In a referenced study of 2,602 patients undergoing therapy for non-muscle invasive bladder cancer, serious complications occurred in less than 5 percent of recipients, with the vast majority encountering only mild cystitis, transient fever, or self-limiting malaise. A comprehensive review of 282 patients presenting with confirmed bacillus Calmette-Guérin toxicity highlighted that while late-onset complications remain largely confined to the genitourinary tract, disseminated infections manifest rapidly, exhibiting a median onset interval of two days post-instillation and an associated mortality rate of 9.9 percent. Miliary tuberculosis developed in approximately one-third of disseminated cases, whereas isolated hepatic involvement occurred in 5.7 percent, consistently characterized by cholestatic liver injury and noncaseating granulomatous inflammation. Because disseminated manifestations stem primarily from a cell-mediated type IV hypersensitivity response in an immunologically sensitized host, and first-line agents like isoniazid and rifampicin require two to seven days to achieve clinical effect, early systemic corticosteroid administration provides vital organ protection.
Subject of Research: Complications of intrarenal BCG immunotherapy including sepsis and hepatitis
Article Title: Gram-negative sepsis and granulomatous cholestatic hepatitis following intrarenal instillation of BCG: a case report and narrative review
Article References: Mihanovic, I., Boban, T., Bozic, D., Glavina Durdov, M., Dolonga, P., Radovic, T., Males Raskovic, N., Duvnjak, M., & Pavicic Ivelja, M. (2026). Gram-negative sepsis and granulomatous cholestatic hepatitis following intrarenal instillation of BCG: a case report and narrative review. African Journal of Urology, 32(1), Article 39. https://doi.org/10.1186/s12301-026-00588-0
Image Credits: AI Generated
DOI: 10.1186/s12301-026-00588-0
Keywords: BCG immunotherapy, Gram-negative sepsis, Granulomatous hepatitis, Urothelial carcinoma, Case report, Liver failure, Mycobacterium bovis, Anti-tuberculosis therapy, Corticosteroids, Ureteral CIS, Gram-negative, sepsis
