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Abstract
BCG, or live attenuated Mycobacterium bovis, intravesical immunotherapy is now an established component of the standard of care for bladder cancer following transurethral resection of bladder tumour. The following case demonstrates the rare complication of disseminated BCG (BCG-osis) that may arise after the aforementioned therapy. Patients at increased risk of this complication include those who are immunocompromised, above the age of 70 and patients who have had traumatic catheterisation. Diagnosis can be made with or without microbiology and management includes a multidrug regimen. It is important to recognise the signs and symptoms of BCG-osis and postpone future intravesical instillation of BCG if there is traumatic catheterisation. Future instillation should be completely discontinued if a patient develops disseminated M. bovis.
- Cancer intervention
- Immunological products and vaccines
- Urinary tract infections
- TB and other respiratory infections
- Urological cancer
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- Cancer intervention
- Immunological products and vaccines
- Urinary tract infections
- TB and other respiratory infections
- Urological cancer
Background
BCG is a live attenuated Mycobacterium bovis that was first used in humans as a tuberculosis (TB) vaccine in the early 1920s.1–3 In 1976, BCG immunotherapy was introduced as the management for non-invasive transitional cell carcinoma of the bladder.1 2 Since then, it has been used as the standard treatment for bladder cancer after transurethral resection of bladder tumour (TURBT) to reduce the risk of recurrence and progression.1–3 Despite its benefits, a rare complication of disseminated M. bovis disease can occur in less than 5% of patients following BCG instillation.2–5 BCG-osis can present as miliary pneumonitis, sepsis, soft-tissue infections or granulomatous hepatitis.1 2 We present a case of culture-confirmed BCG-osis following the patient’s fifth cycle of six planned cycles of BCG intravesical immunotherapy.
Case presentation
A man in his 70s presented to the emergency department (ED) after developing a fever of 39.4 °C, chills, confusion, urinary discomfort and haematuria. Earlier that morning, prior to his presentation, he had three failed attempts of straight catheterisation before receiving his fifth cycle of BCG bladder immunotherapy at his outpatient urology office. After which, he was only able to hold the BCG instillation in place for around 45 minutes. Haematuria was noted following traumatic catheterisation, despite this, the urological team had decided it was necessary to proceed with the instillation. His four prior instillations resulted only in low-grade fevers and urinary discomfort.
His medical history is significant for atrial fibrillation on apixaban, aortic stenosis with aortic valve repair and benign prostatic hyperplasia. He has no prior history of TB, BCG vaccination or travel to endemic countries. Four months prior to his presentation, he was diagnosed with high-grade Ta urothelial carcinoma of the posterior bladder (non-muscle invasive bladder cancer, that is, affecting the innermost layer of the bladder lining) following TURBT and fulguration with instillation of mitomycin.6 One month following this, he had an additional TURBT performed for restaging which demonstrated a complete resection of cancer.
On arrival to the ED, the patient was found to have a maximum temperature of 40.4 °C and a heart rate of 90 beats per minute. His systolic blood pressure remained at 90 mm Hg. His bloodwork was unremarkable except for mild anaemia, mild hyponatraemia, elevated lipase and alkaline phosphatase (ALP). He had no leucocytosis and his kidney function was within normal limits. His urinalysis demonstrated turbid urine, proteinuria, pyuria, haematuria and 1+bacteriuria. Due to the concern for sepsis in the setting of acute bacterial cystitis secondary to traumatic catheterisation, he was started on vancomycin and ceftazidime, and a Foley catheter was placed.
Investigations
CT of the abdomen and pelvis with contrast performed, on the night of admission, showed a thick-walled urinary bladder with intraluminal air, perivesicular fat stranding and a loculated gas collection within the left perivesicular region measuring 3.9×1.8×2.8 cm which was concerning for emphysematous cystitis and a small abscess. A retrograde cystogram, demonstrated in figure 1, was performed the following day which revealed a bladder perforation, not visualised on prior imaging.
Retrograde cystogram axial view (A) and coronal view (B) from presentation demonstrating diffusely thick-walled urinary bladder with thin linear defect within the left posterolateral wall with contrast extravasation/gas collection (red arrow) compatible with bladder perforation.
Another retrograde cystogram, shown in figure 2, was conducted 2 weeks following hospital discharge and revealed a healing bladder perforation. Based on these findings, the urology team determined that removing the Foley catheter was appropriate. A cystoscopy and bladder barbotage were performed in the urology office, 1 month following his discharge from the hospital, which demonstrated significant erythema and inflammation around the left bladder wall consistent with prior bladder perforation and ongoing healing, with no evidence of recurrent urothelial carcinoma. Three months later, he underwent another outpatient cystoscopy and bladder barbotage which demonstrated a well-healed scar and small diverticulum on the left side of the bladder, at the site of his prior resection, which is consistent with his known history of perforation.
Retrograde cystogram axial (A) and coronal view (B) 2 weeks after initial presentation demonstrating a healed left lateral wall perforation of previously seen contrast extravasation (red arrow).
On admission, blood and urine cultures were obtained and later a urine sample was taken for acid-fast bacilli (AFB) smear and culture in addition to sending blood for AFB culture. Blood cultures drawn on admission did not grow any organisms; however, the urine cultures demonstrated a few colonies of Enterococcus faecalis. Growth of AFB was noted after 7 weeks and was identified as Mycobacterium tuberculosis complex on PCR testing. Subsequently, the species was further identified as M. bovis and it was found to be sensitive to rifampin (RIF), ethambutol (EMB) and isoniazid (INH) while being resistant to pyrazinamide. The urine AFB culture remained negative.
Differential diagnosis
Since BCG-osis is a rare condition, it was not initially high on our differential diagnosis. Given the patient’s acute presentation, we first considered a bacterial cause of cystitis. His recent procedure involving BCG instillation raised our concern for common pathogens associated with urological procedures such as Pseudomonas aeruginosa and Staphylococcus aureus, which led to the decision to start broad-spectrum antibiotic coverage with vancomycin and ceftazidime. Pathogens such as E. faecalis and Enterococcus faecium were lower on our differential since the patient’s urological procedure did not involve the rectum.
The initial CT scan of the abdomen and pelvis raised concern for possible emphysematous cystitis. However, after a follow-up retrograde cystogram and extensive consultation with radiology, this seemed less likely, with bladder perforation being a more probable cause of the air detected.
Following discharge, the patient showed an initial clinical response to narrowed antibiotic therapy, as discussed below, making it challenging to completely rule out a bacterial cause. Later, disseminated BCG infection was considered a potential differential diagnosis, particularly given the traumatic catheterisation and systemic symptoms.
Treatment
After initial urine cultures grew E. faecalis, antibiotics were narrowed to ampicillin while inpatient. He was then discharged on hospital day 5, after demonstrating clinical improvement, and was started on amoxicillin to complete a total of 10 days of antibiotics. At the time of his discharge, risks and benefits were weighed and it was our opinion that there was no strong indication for empirically treating with antituberculosis therapy, given his clinical improvement.
Following discharge, the patient reported experiencing night sweats. Given the growth of AFB on AFB blood culture which was identified as M. tuberculosis complex on PCR, an extensive discussion was had with a TB expert at the Global TB institution TB Excellence Center in New Jersey regarding treatment regimen and possible drug interactions with apixaban. The decision was made to start therapy in order to prevent involvement in other locations such as the central nervous system, lymph nodes and abdominal organs. He was started on rifabutin 300 mg oral daily (RIF was avoided due to major interactions with apixaban), INH 300 mg oral daily and EMB 1200 mg daily for 2 months, followed by a continuation phase for 7 more months of rifabutin and INH. He was also started on pyridoxine to prevent peripheral neuropathy associated with INH. His urology team decided not to proceed with any further BCG instillation due to his bladder perforation and disseminated BCG.
Outcome and follow-up
After starting triple therapy, the patient was monitored with a biweekly complete blood count, basal metabolic panel and liver profile which remained within normal limits. He has completed therapy and tolerated all medications well with no complaints including resolution of night sweats. Repeat AFB cultures have shown no growth. There was no specific focus of infection found; however, his fever, chills, night sweats and early onset of symptoms are consistent with systemic disease. He did not have any other systemic disease-associated symptoms such as reactive arthritis or granulomatous hepatitis.
Two months following his hospital discharge, repeat blood work was drawn which was similar to his blood work on admission including mild hyponatraemia, mild anaemia and normal kidney function. His ALP reached a peak of 150 U/L at this time before downtrending and completely normalising 3 months later.
Discussion
The BCG vaccine is a live attenuated strain of M. bovis that is used as immunotherapy in patients with bladder carcinoma in situ and to prevent progression and recurrence.1 4 Between 2005 and 2014, 118 cases of BCG-osis were reported in the USA, most of which were secondary to intravesical immunotherapy.7 8 Patients may present with dysuria, frequency, chills, fatigue, haematuria or fever within 48 hours of a BCG instillation.2
Disseminated BCG infection is a complication of intravesicular injections and occurs in 1%–5% of cases.5 BCG-osis may manifest systemically when it is early onset (≤3 months) or can be localised when it is delayed onset (>3 months).2 5 Systemic disease may present with non-specific symptoms such as persistent fever, malaise, night sweats and weight loss.2–4 It may also present as reactive arthritis, mycotic aneurysm, uveitis, granulomatous hepatitis or meningitis.2–4 Local disease often affects the genitourinary tract and may cause penile lesions, prostatitis and may also affect the renal parenchyma.3 4
Risk factors for BCG-osis include age over 70, traumatic catheterisation, immunosuppression, persistent hematuria after transurethral surgery and active cystitis.3–5 In a study by Heiner and Terris, the complication rate of individuals 70 or older was 48.6% and patients who had complications were significantly older than those without complications (p<0.00001).9 One single-institution series and literature review by Pérez-Jacoiste Asín et al demonstrated that patients who had a prior disruption to their bladder mucosa (eg, traumatic catheterisation) were more likely to develop non-disseminated forms of M. bovis infection (p=0.027).2 Our patient was over the age of 70 and had traumatic catheterisation, which placed him at a high risk for developing BCG-osis. A BCG instillation should be delayed 1–2 weeks in cases of traumatic catheterisation to allow for mucosal healing.4
Diagnosis of BCG-osis can be clinical or with microbiology.3 Pérez-Jacoiste Asín et al found that microbiology confirmed the diagnosis in about 48% of cases.2 A positive stain for AFB was seen in around 25% of cases and positive cultures for mycobacterium were seen in 41% of cases.3 Of the 41% of positive cultures only around 5% of them were from blood cultures and around 24% were from the urine.3 It is also important to note that urine AFB cultures may be falsely positive following BCG instillation given its live attenuated nature, some studies have shown that it may persist in the urine and bladder for up to 16 months after completing the intravesicular instillation of BCG.5 7 In our case, however, there was no AFB growth in the urine; instead, it was found in the blood. This indicates that patients with M. bovis may not always have positive microbiological results to confirm the diagnosis. The sensitivity of AFB smear, mycobacterial culture and PCR is low, and therefore, these methods should not be used to rule out BCG-osis.4 5 10 Additionally, urine cultures have a low positive predictive value (PPV) for identifying M. bovis because most of the colony-forming units are flushed out during the first void after instillation.2 10 It is also important to note that M. bovis has a prolonged incubation period and can take up to 8 weeks to grow, in our case 7 weeks.3 4 Further investigations need to be done to compare the diagnostic yield of blood cultures compared with urine cultures, current literature focuses on its low sensitivity and low PPV, respectively. More conclusive results may be found with biopsy samples, in Pérez-Jacoiste Asín et al they found that 86.3% of biopsied cases revealed granulomatous inflammation; however, current literature lacks comparative studies on the potentially higher yield of newer PCR-based assays.2
Treatment of BCG-osis secondary to intravesical instillation is limited and based on the standard of care for M. tuberculosis.3 5 However, pyrazinamide is not used in the treatment regimen due to its resistance to M. bovis.5 There are no clinical trial data available to guide the optimal treatment approach for BCG-osis. Many regimens have been used including 2 vs 3 drug anti-TB therapy; however, there are not enough data to support which is superior. The mainstay of therapy includes an initiation phase for 2 months using RIF, EMB and INH, followed by a continuation phase of RIF and INH for 7 months.8 Systemic corticosteroids have shown good effects when used adjunctively in patients with severe cystitis and localised disease.4 Treatment should not be delayed if clinical suspicion is high.3
Early empiric therapy has been demonstrated to show good clinical effects; however, there are no sufficient data or study to recommend empiric use.3 This is a growing topic of discussion that requires further investigation for guidance and medical management.3 In our case, early empiric therapy was not used, and only following positive cultures was antimycobacterial therapy initiated with good effect and complete resolution of symptoms. Given that our patient was clinically stable it was appropriate to await culture results before subjecting him to any adverse side effects associated with antimycobacterial therapy. This is something that should also be considered when approaching patients with possible BCG-osis; however, if they are haemodynamically unstable with high clinical suspicion for disseminated M. bovis one should consider empiric therapy.
Patient’s perspective
I was asked to comment on my experience regarding BCG sepsis. I was on my fifth bladder treatment post bladder scraping for bladder cancer. The first four treatments were not pleasant but were tolerable. I was able to hold my urine for two hours after completion of the treatment, as instructed.
On my fifth treatment the first two attempts to place the catheter failed. On the third attempt the catheterization was extremely painful, lengthy, and my wife who was present noted a significant amount of blood coming out of the catheter. The catheter was thought to be in my bladder and the BCG was given. I felt exhausted when the catheter was finally pulled out of my bladder.
I tried to keep from voiding, but I could only hold my urine for about an hour after the treatment. I needed to lie down and rest. My wife was concerned because I was not acting myself and had a fever of 102 degrees. She called the doctor’s office and was instructed to take me to the ER.
In the ER I had a temperature of 104 degrees, and I do not remember much of anything except being admitted to the hospital and being on antibiotics. My recall of the next 3 days was minimal, but on day 3, I started to be more alert. I was told that my bladder was punctured, and the antibiotics seemed to be working.
On day five my fever was down, I was fully alert, and I could go home from the hospital with follow-up with Dr.Shiferaw, an Infectious Disease specialist. She informed me that my blood was found to have BCG in it, and it is possible that it may still be in my blood. She said my case was unusual and she wanted to share it with a TB speciality clinic . After reviewing it with the clinicand the State of Connecticut Health Department, Dr.Shiferaw advised me to receive treatment as if I had tuberculosis. I was then put on a 9-month course of TB medication which I completed recently, and I am doing well.
Learning points
BCG-osis should be suspected in patients presenting with sepsis and/or any risk factors of BCG-osis after any intravesical instillation.
Risk factors of BCG-osis include traumatic catheterisation, active cystitis, persistent gross haematuria following transurethral surgery and age over 70.
Diagnosis can be made with or without acid-fast bacillus cultures.
It is highly recommended to delay instillation for a few weeks following traumatic catheterisation; and in cases of BCG-osis, further instillation should be suspended.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: CS, UJ and BS. The following author gave final approval of the manuscript: BS.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.