Uncommon but Clinically Significant: Bacillus Calmette-Guerin (BCG) Infection of the Urinary Tract and its Impact on Quality of Life

Background

The intravesical administration of bacillus Calmette-Guerin (BCG), an attenuated live strain of Mycobacterium bovis, is an effective and widely used immunotherapy for superficial bladder cancer. Intravesical BCG is also an option for appropriately selected patients with intermediate-risk disease. It is generally well tolerated, but complications after intravesical BCG instillation can occur. The frequency of BCG infection is relatively rare [1], with a range of 1% to 5% [2,3]. It is said that approximately 2.9% of BCG-treated patients discontinue immunotherapy owing to a genitourinary or systemic BCG-related infection [4]. BCG infection can take the form of a localized infection, such as in the urinary tract, or of a systemic infection. It often presents with systemic symptoms, but the urinary tract, including the bladder and prostate, is most frequently affected in localized cases. Treatment is often combined with anti-tuberculous agents, except for pyrazinamide, and there are no guidelines and no fixed duration of treatment. Therefore, case reports and literature reviews are relied upon to determine the choice of therapeutic agents and duration of treatment. We report 2 cases of locally localized BCG infection.

Case Reports

CASE 1:

A 77-year-old man with a bladder tumor underwent transurethral resection of the bladder tumor (TURBT); invasive urothelial carcinoma was diagnosed (HG; high grade, pT1, INFb, ly, v0, CIS+) and was followed by intravesical BCG (Immunobladder^®, Japan BCG Laboratory, Japan).

His second TURBT was negative. After induction therapy of BCG, he underwent a cystoscopy, which showed 1 small flat papillary daughter tumor near the left ureter that had previously been seen before BCG induction. At 2 or 3 days after the tenth bladder BCG instillation, the patient had urinary urgency and frequency, without fever. He was treated with a 14-day course of levofloxacin, which was ineffective. Two months after completing the second cycle, his urinary symptoms deteriorated. Therefore, he underwent a cystoscopy, which showed redness and swelling of the bladder wall, without any findings of recurrence of bladder cancer.

On examination, his vital signs were within the normal limit. He had tenderness on the prostate, with warmth. There was no costovertebral angle tenderness. His complete blood count, renal function, liver function, and electrolyte test results were all unremarkable. His urinalysis showed pyuria and nitrites were negative, and urine occult blood was positive. The urine culture was positive for coagulase-negative staphylococcus, and an acid-fast bacterium culture of urine was negative. A computed tomography (CT) scan of the abdomen with contrast revealed thickening of the bladder (Figure 1), without any abnormal findings of other abdominal organs. An X-ray and CT scan of the chest showed no abnormalities.

Based on physical examinations, images, and treatment course, we tentatively diagnosed BCG infection of the bladder and prostate.

Treatment with isoniazid 300 mg (5 mg/kg) orally (p.o.) every 24 h, rifampicin 600 mg (10 mg/kg) p.o. every 24 h, and ethambutol 750 mg (15 mg/kg) p.o. every 24 h was started, as local BCG infection was confined to the bladder and prostate. There were no significant adverse events from the anti-tuberculosis agents. His medication adherence was good. Two months after treatment, his symptoms did not subside, and he underwent magnetic resonance imaging (MRI) of the prostate with contrast for further evaluation of the prostate lesion. MRI showed a high signal with a diffusion-weighted image (Figure 2) and diffuse restriction with apparent diffusion coefficient mapping (Figure 3) on the right lamina of the prostate, suggesting granulomatous prostatitis. The same area showed a low signal on T2-weighted images (Figure 4). A prostate biopsy was performed to closely examine whether the prostate lesion noted on MRI was an abscess or a granulomatous lesion and revealed the presence of granuloma, which contained epithelioid macrophages, Langhans giant cells, and lymphocytes (Figure 5). Treatment with anti-tuberculous agents was continued for BCG infection, including of the prostate and bladder. Six months after treatment, his urinary urgency and frequency did not improve, and his quality of life was significantly impaired; therefore, he underwent total resection of the bladder and prostate. Pathological examination of the resected bladder showed an invasion of urothelial carcinoma. An incidental carcinoma (adenocarcinoma) was found in the prostate, surrounded by many epithelial granulomas, with epithelioid macrophages and some necrosis.

CASE 2:

An 84-year-old man with a bladder tumor underwent TURBT; bladder cancer was diagnosed (non-invasive urothelial carcinoma, high grade, pTis) and was followed by intravesical BCG therapy (Immunobladder^®, Japan BCG Laboratory, Japan). After induction therapy of BCG, he underwent a cystoscopy, which revealed suspicion of bladder cancer; therefore, TURBT was performed. Pathology of the resected specimen showed urothelial carcinoma in situ, and a second BCG therapy was planned. A few days after the second cycle of bladder BCG instillation, he developed urinary frequency and was tentatively diagnosed with a urinary tract infection and treated with a 7-day course of levofloxacin, which was ineffective. Before starting levofloxacin, a urine culture was taken and was positive for Enterococcus faecalis, which was sensitive to levofloxacin. The patient continued intravesical BCG instillation therapy, and urine occult blood and hematuria were present throughout this period. After the third cycle of intravesical BCG instillation, his urinary symptoms deteriorated. A cystoscopy was performed at this point, and although there were no findings suggestive of recurrence of cancer, the bladder mucosa was intensely red and the urine cytology showed class II, which indicated inflammatory change.

On examination, his vital signs were within the normal limit, he had no tenderness of the prostate. His complete blood count, renal function, liver function, and electrolytes were all unremarkable. His urinalysis showed pyuria and nitrites were negative. Urine culture results were positive for Proteus mirabilis and E. faecalis, which were also sensitive to levofloxacin, and an acid-fast bacterium culture of urine was negative. A CT scan of the abdomen with contrast showed thickening of the bladder wall and ureter and atrophied prostate (Figure 6). A chest CT scan showed no evidence of active tuberculosis. BCG infection of the bilateral ureter and bladder was tentatively diagnosed, based on the patient’s symptoms and clinical course.

Treatment consisted of isoniazid 300 mg (5 mg/kg) p.o. every 24 h, rifampicin 600 mg (10 mg/kg) p.o. every 24 h, and ethambutol 750 mg (15 mg/kg) p.o. every 24 h. Two weeks after starting the anti-tuberculosis agents, he developed a disseminated maculopapular rash. Rifampicin was withdrawn, as a drug suspicious of inducing rash, until the rash disappeared. After rifampicin was withdrawn, rifabutin 300 mg was added, and treatment was continued with 3 anti-tuberculous agents. Four months after the start of the treatment, he still had urinary symptoms; therefore, a CT scan of the abdomen with contrast was performed to follow up the treatment course. Although the thickening of the bladder wall remained, the ureter lesion tended to improve (Figure 7). Treatment was continued, and 13 months after the start of treatment, his symptoms almost disappeared. A CT scan of abdomen with contrast showed no significant thickening of the bilateral ureters and bladder, and MRI of the prostate without contrast showed no extension of the lesion into the prostate; therefore, the treatment with anti-tuberculous agents was terminated.

Discussion

Bladder cancer is the tenth most common cancer in the world, and the incidence is gradually increasing, especially in developed countries [5]. Intravesical therapy permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following transurethral resection of all visible bladder tumors. BCG is a live attenuated form of M. bovis and is the most used agent for intravesical therapy. Intravesical BCG is also an option for appropriately selected patients with intermediate-risk disease [6–8]. Intravesical BCG triggers a variety of local immune responses that can persist for several months and appear to correlate with antitumor activity [9]. In general, intravesical BCG is usually well tolerated, but it sometimes causes severe local and systemic complications. The localized disease typically presents with delayed-onset infection, as in our 2 cases involving infection of the genitourinary tract, including cystitis, bladder contracture, granulomatous prostatitis, epididymal-orchitis, testicular abscess, pyelonephritis, and ureteral stricture.

The localized disease will be suspected with bladder irritation, such as dysuria, and frequency after intravesical BCG instillation. The definitive diagnosis of BCG infection can be established via positive M. bovis BCG culture of tissues; however, the sensitivity of acid-fast bacteria stain and culture is subject to limitations. The tissue culture positive rate is 40.9%, and even in disseminated infection, the tissue culture positive rate is not high (40–60%) [10]. Therefore, in the appropriate clinical and epidemiologic setting and in the absence of evidence for an alternative etiology of these findings, a presumptive diagnosis can be made in the setting of histopathology from an involved site demonstrating granulomas. Although M. bovis was not isolated from the culture of urine and tissue in either of our 2 cases, the presumptive diagnosis of BCG infection was made based on the presence of granuloma with epithelioid macrophages in the prostate specimen in the first case and the clinical symptoms and images and response to treatment in the second case. In the first case, the MRI was closely examined for conditions other than BCG infection of the bladder that might explain the symptoms, and a prostatic lesion was found. This case suggests that further examination is more important when the culture is negative.

As for the treatment of BCG infection, the optimal regimen is uncertain. Treatment is based on a combination involving isoniazid, rifampin, and ethambutol, but not pyrazinamide, because M. bovis is intrinsically resistant to pyrazinamide [11,12]. In our 2 cases, both patients were treated with 3 drugs: isoniazid, rifamycin, and ethambutol. Although there is no fixed duration of treatment, the median duration of treatment in the previous literature is 6 months [2]. In the first case, the resected prostate revealed an incidental carcinoma, with a background of numerous epithelial granulomas, some with necrosis despite 6 months of anti-tuberculous treatment. M. bovis BCG is often susceptible to most anti-mycobacterial drugs, except pyrazinamide and cycloserine [13]. Unfortunately, the tissue culture was negative for acid-fast bacilli; therefore, the susceptibility of this M. bovis BCG is unknown. However, resistance to the agents that we used is suspected. Moreover, the penetration of antimicrobial agents to the prostate is generally poor [14], and there are few data on prostate penetration of anti-tuberculous agents. Therefore, the failure of treatment in the first case may be associated with prostate penetration of anti-tuberculous agents. On the other hand, fluoroquinolones have been shown to have good penetration to the prostate [14], and in cases like our first one, fluoroquinolones may be a reasonable option.

In the second case, the treatment was continued for more than 6 months; however, the symptoms tended to improve with the current treatment, and therefore we continued treatment for 13 months, when symptoms improved. Previous reports have shown that even if the infection is systemic, treatment with anti-tuberculosis agents is often continued for approximately 6 months [2]. Although there is no fixed duration of treatment for BCG infection, our case suggests that the duration of treatment, even for local infections, needs to be individualized.

In addition, surgical resection can be performed when BCG-infected lesions extend to vital organs, such as aortic aneurysms, or when epididymitis is difficult to control with conservative treatment with anti-tuberculosis drugs [10]. In our first case, the infected organ was not a vital organ, and it may not have been necessary to perform total resection; however, the patient’s symptoms did not improve by anti-tuberculous agents only. Localized BCG infections, especially in genitourinary organs, are often treated conservatively with anti-tuberculosis drugs only, and surgery may be performed if there is abscess formation in the testes or prostate. In our first case, although there was no abscess formation, the surgery was performed because the indication that the patient’s quality of life was severely impaired. Surgery significantly improved the patient’s quality of life, and this case demonstrates that surgery can be an option when symptoms interfere with quality of life.

Conclusions

BCG infection is a rare complication of intravesical BCG instillation, and its phenotype is diverse, ranging from systemic to localized. Treatment consists of a combination of several anti-tuberculosis drugs; however, the duration of treatment can last several months and should be individualized. Surgical re-section may be an option if anti-tuberculosis agents alone fail to control the disease.