Late-onset Mycobacterium bovis prosthetic knee infection following intravesical BCG therapy

Summary

Intravesical BCG is a common treatment for non-muscle-invasive bladder cancer but can rarely cause serious infections. We report the case of a man in his late 60s with bilateral total knee replacements who developed knee pain 18 months after receiving BCG therapy. Evaluation revealed mildly elevated inflammatory markers, negative routine bacterial cultures and acid-fast culture positive for Mycobacterium bovis, resistant to pyrazinamide. Imaging demonstrated periprosthetic lucency without overt mechanical failure. Following multidisciplinary discussion, the patient was treated with isoniazid, rifabutin and pyridoxine without surgical intervention. His symptoms resolved and he remained free of infection at 3 years of follow-up. Few cases of BCG-related prosthetic knee infections have been described. This case underscores that prosthetic joint infection can occur long after BCG therapy and that carefully selected patients may be managed successfully with prolonged antimycobacterial therapy.

Background

Intravesical BCG has been established as an effective option for treatment and inhibition of progression and recurrence of non-muscle-invasive bladder carcinoma (NMIBC).¹ Although intravesical BCG is generally considered safe, infectious complications occur in approximately 1%–5% of patients and can include both local and systemic manifestations.² Peri-prosthetic seeding and infection is a rare but serious complication of intravesical BCG treatment of NMIBC.¹

BCG is an attenuated strain from Mycobacterium bovis through the deletion of region of difference 1 (RD1).^{1 3} Although deletion of the RD1 region attenuates M. bovis by removing its most virulent genes, other pathogenic factors such as cell wall lipids, prolene-glutamic acid (PE) proteins, prolene-prolene-glutamic acid (PPE) proteins and intact early secreted antigenic target 6 secretion system X (ESX) remain, which may explain why infectious complications of BCG can still occur.^{1 3} The mechanism with which BCG treats superficial urothelial carcinoma of the bladder has yet to be determined, but the prevailing theory revolves around the idea that BCG stimulates a localised non-specific inflammatory response that leads to subsequent shedding of tumour cells within the bladder.⁴ Clinical and experimental data have shown a strong association between a robust immune response and potent antitumour activity.⁴

We present a case of disseminated BCG prosthetic joint infection of a total knee arthroplasty following BCG treatment of superficial urothelial carcinoma of the bladder. There have only been three other such cases reported in the literature involving total knee arthroplasties.^5–7

Case presentation

A previously healthy man in his late 60s received bilateral total knee arthroplasties (Table 1). Approximately 19 months later, the patient was diagnosed with superficial urothelial carcinoma of the bladder and initiated intravesical therapy. The patient was treated with a single 81 mg dose of intravesical BCG followed by weekly instillations of 40 mg of mitomycin, which resulted in regression of the bladder tumour and no evidence of recurrence on follow-up cystoscopy.

Approximately 16 months after BCG therapy (3 years after arthroplasty), the patient developed bilateral knee pain and was referred to infectious disease by the orthopaedic surgeon who had performed his bilateral total knee arthroplasties. Approximately 2 months later, he presented to the infectious disease clinic. At the time of this visit, he denied systemic symptoms such as fever, chills or weight loss. Vital signs included a temperature of 36.9°C, blood pressure of 163/76 mmHg, pulse of 61 beats/min and weight of 107.1 kg. He reported bilateral knee pain, left greater than right. Physical examination revealed a normal gait, no cyanosis, normal movement of all extremities and intact muscle strength and tone without joint instability. The surgical incisions remained intact, and the knee joints were mildly warm with minimal effusion. Arthrocentesis was performed at this visit.

Investigations

Baseline laboratory evaluation was obtained to assess for inflammatory and systemic involvement. Haemoglobin A1c was 6.1%. Complete blood count and liver function tests were within normal limits. At presentation, inflammatory markers were only mildly elevated: erythrocyte sedimentation rate (ESR) 32 mm/hour (reference 0–20) and C-reactive protein (CRP) 1.6 mg/dL (reference 0.0–1.0), with a normal procalcitonin of 0.1 ng/mL. These findings suggested a mild inflammatory response without evidence of acute systemic infection. With antimycobacterial therapy and clinical improvement, the ESR subsequently fell to 16 mm/hour on follow-up, paralleling symptom resolution, while CRP and procalcitonin remained low. This trend is summarised in the timeline.

Synovial fluid aspiration of the right knee was performed. Gram stain demonstrated no white blood cells or organisms, and routine bacterial cultures were negative, lowering suspicion for typical bacterial prosthetic joint infection. Detailed synovial fluid cell count, differential, protein and glucose measurements were not available in the medical record, which represents a limitation in fully characterising the inflammatory profile of the effusion. Acid-fast bacilli staining was negative; however, acid-fast culture subsequently grew M. tuberculosis complex.

Further testing was performed to clarify species identification. The isolate was sent to National Jewish Health for genotypic analysis, which confirmed M. bovis (BCG strain). Susceptibility testing demonstrated sensitivity to isoniazid, rifampicin, ethambutol, streptomycin and kanamycin. An H57D mutation was detected, consistent with intrinsic pyrazinamide resistance. QuantiFERON-TB Gold testing was negative, supporting the absence of latent or active M. tuberculosis infection.

Imaging was reviewed serially to evaluate mechanical integrity and the extent of involvement. A three-phase bone scan of both knees, performed approximately 10 months after arthroplasty and predating BCG therapy, showed increased periprosthetic tracer uptake consistent with expected post-surgical remodelling, without scintigraphic evidence of osteomyelitis. A repeat three-phase bone scan, obtained for bilateral knee pain approximately 3 months before presentation, demonstrated a pattern typical for arthroplasty approximately 3 years out and was not suggestive of periprosthetic infection or loosening. CT of the right knee, obtained approximately 7 months after presentation, subsequently demonstrated periprosthetic lucency and demineralisation without gross mechanical failure (detailed in Outcome and follow-up). These findings raised concern for periprosthetic infection versus loosening but did not demonstrate gross mechanical failure. No evidence of disseminated BCG infection was identified on systemic evaluation.

Differential diagnosis

Late-onset pain after total knee arthroplasty raised concern for both mechanical and inflammatory causes. Aseptic loosening was considered given the chronicity and later imaging demonstrating periprosthetic lucency; however, the presence of joint effusion and mild warmth prompted evaluation for infection. Low-grade bacterial prosthetic joint infection due to indolent organisms was assessed with synovial fluid Gram stain and routine bacterial cultures, which were negative, lowering the likelihood of typical bacterial prosthetic joint infection (PJI). Crystal arthropathy and inflammatory arthritis were also considered because they can present with pain and effusion in the absence of systemic symptoms, although no clinical features suggested an acute crystal flare and symptoms were persistent rather than episodic. Given the history of intravesical BCG therapy, reactive BCG-related synovitis and mycobacterial infection were specifically considered. Although acid-fast staining was negative, mycobacterial culture from synovial fluid grew M. tuberculosis complex and subsequent genotyping confirmed M. bovis (BCG strain), establishing the final diagnosis of BCG-related prosthetic joint infection.

Timeline

The timeline of the patient’s diagnosis, treatment and subsequent follow-up is summarised in table 1, including the diagnosis of bladder cancer and intravesical BCG therapy preceding the development of BCG-associated prosthetic joint infection.

Table 1. Timeline of present case.

Time point	Event/finding
Arthroplasty (baseline)	Bilateral total knee arthroplasty
~10 months after arthroplasty	Three-phase bone scan (both knees) for bilateral knee pain, ~10 months after arthroplasty and before BCG therapy: increased periprosthetic tracer uptake consistent with expected post-surgical remodelling; no scintigraphic evidence of osteomyelitis
~19 months after arthroplasty (BCG exposure)	Diagnosis of non–muscle-invasive bladder cancer; single 81 mg intravesical BCG instillation followed by weekly 40 mg mitomycin
~16 months after BCG (~3 months before presentation)	Repeat three-phase bone scan for bilateral knee pain; pattern typical for arthroplasty ~3 years out, not suggestive of periprosthetic infection or loosening
Presentation (~18 months after BCG)	Presentation to infectious disease clinic; inflammatory markers: ESR 32 mm/hour, CRP 1.6 mg/dL, procalcitonin 0.1 ng/mL; right knee arthrocentesis performed
Within weeks of presentation	Acid-fast organisms detected on right-knee synovial fluid culture
~1 month after presentation	Mycobacterium tuberculosis complex identified (reference laboratory)
~2 months after presentation	Susceptibilities: pyrazinamide resistance (pncA mutation); susceptible to isoniazid, rifampicin and ethambutol
~4 months after presentation	Bilateral knee re-aspiration: left knee inflammatory synovial fluid but bacterial, anaerobic, fungal and mycobacterial cultures all negative; repeat right-knee cultures negative. Species confirmed as M. bovis (BCG strain) by genotyping
Treatment initiation	Antimycobacterial therapy started and continued for 9 months: isoniazid 300 mg a day, rifabutin 150 mg two times a day, pyridoxine 25 mg a day
~7 months after presentation	CT of the right knee: ~9 mm lucency about the tibial component, focal distal-femoral trabecular loss (uncertain significance), diffuse demineralisation and joint effusion; no periprosthetic fracture or dislocation
~3 years after presentation	Symptoms resolved with no evidence of recurrent infection (~3 year follow-up); ESR improved to 16 mm/hour
~8 years after presentation	Long-term follow-up right-knee radiographs (figure 1): prosthesis in situ and well-fixed, without progressive periprosthetic lucency or osteolysis

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Treatment

Management of PJI typically involves surgical intervention in addition to antimicrobial therapy. Current Infectious Diseases Society of America (IDSA) guidelines recommend debridement with implant retention or staged revision for most bacterial PJIs. However, the evidence base and guideline recommendations primarily address infections caused by typical bacterial pathogens, and limited guidance exists regarding atypical mycobacterial prosthetic joint infections.

In this case, several factors influenced the decision to pursue medical management alone. The patient presented with an indolent clinical course without systemic instability. Inflammatory markers were only mildly elevated, and routine bacterial cultures were negative. Imaging demonstrated periprosthetic lucency but did not show gross mechanical failure or definitive loosening requiring urgent revision. The isolate was confirmed as M. bovis (BCG strain), an organism known to exhibit slower progression compared with typical pyogenic PJI pathogens and with predictable susceptibility to antimycobacterial therapy.

The case was discussed in a multidisciplinary setting. Given the patient’s history of coronary artery disease and the absence of acute prosthesis failure, the risks of surgical intervention were weighed against a trial of prolonged targeted antimycobacterial therapy. A decision was made to initiate antibiotic therapy with close clinical and radiographic monitoring. The patient demonstrated sustained clinical improvement and remained free of infection at the 3-year follow-up.

While surgical management remains standard for most PJIs, this case illustrates that carefully selected patients with indolent BCG-related infection may be considered for non-operative management under close multidisciplinary supervision.

Because management with antimycobacterial therapy alone constituted, in effect, a trial of non-operative treatment, criteria for escalation to surgery were defined at the outset and monitored throughout follow-up. Operative intervention—debridement with implant retention or staged revision—would have been pursued in the event of worsening pain or functional decline, progressive periprosthetic lucency or osteolysis on serial imaging, a rising or persistently elevated inflammatory-marker trend, persistent microbiologic or clinical evidence of infection despite therapy, or any evidence of implant instability or loosening. None of these features developed, and the patient was managed non-operatively throughout.

Outcome and follow-up

Resulting cultures of the right knee aspirate grew M. bovis that was resistant to pyrazinamide, a feature that diagnostically distinguishes it from M. tuberculosis. With concern for M. bovis septic arthritis, the patient was started on oral isoniazid 300 mg a day, pyridoxine 25 mg a day and rifabutin 150 mg two times a day, which he completed for a total of 9 months. Although the isolate was susceptible to rifampicin, rifabutin was selected in its place to minimise drug–drug interactions: rifampicin is a potent inducer of cytochrome P450 enzymes (notably CYP3A4), whereas rifabutin is a substantially weaker inducer, making it a safer companion agent given the patient’s coronary artery disease and concomitant cardiac medications.

Follow-up CT imaging of the right knee, obtained approximately 7 months after presentation, demonstrated a 9 mm lucency around the tibial component at the medial tibial plateau, extending along the anterior, posterior and lateral margins. Also reported was a focal loss of bony trabecula in the distal femur abutting the posterior margin of the prosthesis, which is an atypical location for loosening of a prosthesis or an infection. Additional findings included joint effusion with diffuse demineralisation and a lack of periprosthetic fracture or dislocation.

At 3-year follow-up, the infection had subsided, and the patient reported feeling well overall.

Long-term follow-up radiographs of the right knee (anteroposterior, skyline and lateral views) obtained approximately 8 years after presentation showed the femoral, tibial and patellar components to remain in situ and grossly well-aligned, without progressive periprosthetic lucency, osteolysis, component migration, fracture or dislocation, consistent with a stable, well-fixed prosthesis (figure 1).

Figure 1. Long-term follow-up plain radiographs of the right total knee arthroplasty (approximately 8 years after presentation): (A) anteroposterior, (B) skyline/patellar and (C) lateral views. The femoral, tibial and patellar components remain in situ and grossly well-aligned, without progressive periprosthetic lucency, osteolysis, component migration, fracture or dislocation, consistent with a stable, well-fixed prosthesis.

Taken together, the imaging evolved from non-specific scintigraphic findings on the two early bone scans, through the periprosthetic lucency, diffuse demineralisation and joint effusion demonstrated on CT at 7 months, to durable radiographic stability on long-term plain films, with no progression of lucency or osteolysis to indicate implant failure or uncontrolled infection. This radiographic course paralleled the patient’s clinical improvement and the fall in inflammatory markers, supporting the success of non-operative management.

Discussion

Due to the rarity of BCG dissemination resulting in prosthetic joint infection, only nineteen cases of M. bovis prosthetic infections related to intravesical BCG, including the present case, have been reported in the literature. These are described in table 2. While this remains an exceedingly rare complication, it is important for providers to recognise the possibility in patients presenting with unexplained joint symptoms after BCG therapy, even years later. Fourteen involved total hip arthroplasties, four involved total knee arthroplasties and one involved the shoulder.^{1 5–21}

Table 2. Literature review of past cases.

Author	Gender	History of original procedure	Presentation	Pertinent medications	Orthopaedic treatment	Outcome
Present case	Male	Bilateral TKA | 3 years before presentation	Bilateral knee pain with infection present in right knee	Oral rifabutin 150 mg two times a day, isoniazid 300 mg once a day and pyridoxine HCL 25 mg once a day	No surgical intervention was needed	No signs of infection after 3 years
Pelt et al7	Male	TKA | 16 weeks before presentation	Initial swelling and pain with ambulation after a fall Roughly 16 months passed before Mycobacterium bovis diagnosis was reached	Rifampicin, isoniazid and ethambutol (9 months) levofloxacin therapy (6 weeks)	DAIR-strategy, irrigation and medial arthrotomy repair; large effusion present 6 weeks postoperatively; repeated DAIR-strategy with no obvious signs of infection; pain and effusion recurred 12 weeks postoperatively; revision was performed 1 year later with debridement and drain implantation	Complete resolution of joint effusion at 6-month and 9-month follow-up visits
Rispler et al5	Male	Uncemented TKA | 5 years before presentation	Progressive knee stiffness	Rifampicin 600 mg and isoniazid 300 mg a day for 12 months	No surgical intervention was needed	No signs of infection at 7.5-year follow-up
Chazerian et al6	Male	TKA | 9 years before presentation	Acute arthritis, fevers	Antituberculosis medications for 2 years	Two-stage TKA revision	Asymptomatic at 2-year follow-up with persistent bladder cancer
Aitchison et al1	Male	THA with three revisions ending in 2001 | 12 years before presentation	Fluid-filled mass on posterolateral buttock, night sweats, anorexia, weight loss, malaise and fatigue	Rifampicin 600 mg, isoniazid 300 mg, ethambutol 1 g, pyrazinamide 2 g and pyridoxine 25 mg a day (4 months); rifampicin, isoniazid, ethambutol and pyridoxine (last 11 months)	Debridement and washout; two more washouts 3 and 4 months after presentation; prosthesis was retained.	No infection 27 months after initial presentation: discharging sinus, prescribed clindamycin for suppression
Williams et al8	Male	Uncemented THA | 9 years before presentation	Collection over anterior thigh	Rifampicin 300 mg bd, isoniazid 150 mg bd (12 months), ethambutol 1200 mg a day (3 months), moxifloxacin 400 mg a day (9 months)	Revision of acetabular linear and head components, washout and debridement 4×, and repeat revision of modular components	No signs of infection at 24 months with stable components
Guerra et al9	Male	THA | 6 years before presentation	6 months of hip pain with sweats and rigours	Rifampicin and isoniazid (6 months); restarted at 9 months after positive biopsy	One-stage revision	Patient passed from lung carcinoma before treatment was completed.
Segal and Krauss10	Male	Cemented THA | 18 years before presentation	2 years of progressive hip pain	Rifampicin 600 mg (12 months), isoniazid 300 mg, ethambutol 1200 mg	Two-stage THA revision after 12 months of therapy	No signs of infection or implant loosening at 36 months
Registad and Siewers11	Male	Cemented THA | 10 years before presentation	Groin pain with watery pus in joint space	Rifampicin 600 mg, isoniazid 300 mg (12 months) pyrazinamide 1.5 g (6 months); isoniazid 200 mg a day (24 months)	One-stage revision uncemented THA	Pain-free and mobile at 30 months
Gomez et al12	Male	THA | 6 years before presentation	Hip pain	Rifampicin and isoniazid (12 months) after second revision	One-stage revision of THA; second stage at 9 months to replace femoral head	No sign of infection after 12 months
Metayer et al13	Male	Uncemented THA | 9 years before presentation	Hip pain, painless mass in inguinal fold	Rifampicin, ethambutol, isoniazid for 12 months; moxifloxacin stopped after 30 days	One-stage revision THA after 6 months of antibiotics and removal of mass
Srivastava et al14	Female	THA | 6 years before presentation	Hip pain	Antituberculosis medication for 9 months	Two-stage THA revision	No sign of infection after 5 months
Nguyen et al15	Male	THA | 31 years before presentation	Swelling of left thigh with purulent discharge, chills, rigours and fever	Oral rifampicin 600 mg a day, isoniazid 300 mg a day, pyrazinamide 1500 mg a day, ethambutol 1200 mg a day and vitamin B6 50 mg a day	DAIR-strategy	No signs of infection after 12 months
Chundi and Didwania16	Male	THA | >31 years before presentation; revision 12 years later; TKA | 19 years later with revision	Hip pain and weakness resulting in use of walker	Rifampicin, isoniazid, ethambutol and pyridoxine for 3 months	Revision of acetabular component	Therapy was discontinued due to poor tolerance and patient preference
Storandt and Nagpal17	Male	THA | 27 years before presentation	Hip pain followed by surgical revision.	Rifampicin, isoniazid and ethambutol for 6 months	One-stage revision before PJI diagnosis which worsened the symptoms; some symptoms were similar to those following BCG instillation	Asymptomatic at 9 months
Goedertier and Sioen18	Male	THA | 19 years before presentation with a revision 6 months before	Hip pain	Rifampicin 300 mg two times a day, isoniazid 300 mg a day and ethambutol 400 mg three times a day for 12 months	Two-stage revision	While asymptomatic, the patient walks with a cane
Patel and Elzweig19	Male	THA | 34 years before presentation with a revision 17 years before	Hip pain with fluid collection over left lateral hip	Rifampicin, isoniazid and ethambutol (2 months); rifampicin and isoniazid the following 10 months	Two-stage revision	Asymptomatic at 1 year
Riste et al20	Male	THA | 8 years before presentation	Hip pain associated with soft tissue mass, fluid collection with irregular serous discharge, weight loss	Rifampicin, isoniazid, ethambutol and moxifloxacin for 6 months	Two-stage revision	Asymptomatic following revisions and medication
Stern et al21	Male	Shoulder | 4 years before presentation	Shoulder pain	Rifampicin, isoniazid and ethambutol	No surgical intervention was taken	Patient elected to enter hospice care and expired 13 days after discharge

DAIR, debridement, antibiotics, and implant retention strategy; PJI, prosthetic joint infection; THA, total hip arthroplasty; TKA, total knee arthroplasty.

In 18 of 19 cases, patients received the total joint replacement before treatment for bladder cancer. In only one case, the total joint replacement took place after bladder cancer treatment.⁷ The time between receiving intravesical BCG treatment and signs of infection ranged from 2.5 to 70 months.^{6 9} This means that traces of Mycobacterium from BCG treatments resided in patients’ bodies for extensive time periods. This prolonged latency supports the hypothesis that viable organisms may persist in a dormant state before reactivation. Previous research showed that presence of BCG in patients was still detected in the bladder at 24 months after the last BCG treatment.²²

The widespread use of BCG in the management of NMIBC underscores the clinical relevance of these rare complications. In a study of 5410 patients with NMIBC, 93.1% received BCG as first-line therapy. Of these, 69.8% did not complete an adequate induction or maintenance regimen, and 46.4% ultimately required transurethral resection of bladder tumour.²³ Given how commonly BCG is used in urologic oncology, even infrequent complications such as prosthetic joint infection remain clinically important. Notably, our patient developed infection despite receiving only a single instillation of BCG followed by mitomycin, which suggests that even limited exposure can lead to dissemination in susceptible individuals.

Another question arises from the clinical presentation. Although the patient reported bilateral knee pain that was worse on the left, only the right knee aspirate grew M. bovis. The contralateral (left) knee was also investigated: it was aspirated approximately 4 months after presentation and yielded inflammatory synovial fluid (moderate leucocytes with cellular debris), but bacterial, anaerobic, fungal and mycobacterial cultures were all negative, as were repeat right-knee cultures at that time. Microbiologic confirmation of M. bovis was therefore obtained from the right knee only. This discrepancy may reflect differences in bacterial burden between joints, sampling variability or the possibility that the left-sided symptoms represented a reactive or culture-negative inflammatory process rather than culture-proven infection.

There are three main treatment methods for disseminated BCG infections: DAIR (debridement, antibiotics and implant retention strategy), one or two-stage implant revision and antituberculosis medications with no surgical intervention. In standard prosthetic joint infections caused by typical bacterial pathogens, current IDSA guidelines recommend surgical management in conjunction with antimicrobial therapy. However, guidance specific to atypical mycobacterial prosthetic joint infections remains limited, and published cases demonstrate heterogeneous management strategies.

In the present case, the decision to pursue medical management alone was individualised and made after multidisciplinary consideration. The patient demonstrated an indolent clinical course without systemic instability, inflammatory markers were only mildly elevated and imaging did not demonstrate gross mechanical failure requiring urgent revision. The confirmed susceptibility profile of M. bovis further supported a trial of prolonged targeted antimycobacterial therapy with close clinical monitoring.

An additional factor that has been raised is whether the strain of BCG may influence complication rates. Currently, seven strains are commonly used worldwide for NMIBC treatment, all of which share the deletion of the RD1 region.^{24 25} Available studies suggest little to no difference in complication profiles between strains, though direct comparative evidence remains limited. This indicates that patient-specific factors and the persistence of viable organisms may play a greater role than strain variability in the development of disseminated infections.

Although rare, the threat of BCG PJIs is something patients and medical professionals should be aware of. While intravesical BCG is most often managed by urologists, its systemic complications may present to a wide range of specialties. Beyond orthopaedics, prosthetic valves, vascular grafts and other implanted devices could theoretically be at risk, which highlights the need for cardiology, vascular surgery and other specialties caring for patients with prostheses to recognise this association. Increased awareness across disciplines may shorten the time to diagnosis and help prevent unnecessary revision surgeries or prolonged morbidity.

Conclusion

Prosthetic joint infections from intravesical BCG are very uncommon but should be considered when patients with prior arthroplasties present with unexplained joint pain. While surgical intervention remains the standard of care for most prosthetic joint infections, this case illustrates that carefully selected patients with indolent BCG-related infection may be managed successfully with prolonged antimycobacterial therapy under close multidisciplinary supervision. Awareness of this complication can help with earlier diagnosis and more targeted treatment.

Learning Points.

• This case shows successful management of an indolent BCG-related infection without the need for surgical intervention.

• The timeline between receiving intravesicular BCG and presentation of signs of infection ranges from 2.5 to 70 months. This shows that traces of BCG treatment can remain for extensive time periods.

• Prosthetic joint infections from intravesical BCG are not common, but should be considered in patients with prior arthroplasties present with unexplained joint pain.

• Increased awareness across disciplines may shorten the time to diagnosis and prevent unnecessary revision surgeries or prolonged morbidity.