Mycobacterium bovis prosthetic joint infection following intravesical instillation of BCG for bladder cancer

Abstract

A 91-year-old man with a history of intravesicular BCG therapy for recurrent bladder cancer and bilateral total hip arthroplasty (THA) presented with left hip pain. He was noted to have a fluid collection over the left lateral hip and hip X-ray showed loosening of the prosthetic hip stem indicative of a prosthetic joint infection (PJI). He subsequently underwent removal of the THA and insertion of an antibiotic spacer. He was discharged on intravenous ceftriaxone for presumed culture negative PJI. Intraoperative acid fast bacillus culture later grew Mycobacterium tuberculosis complex, which was then differentiated to M. bovis. The M. bovis infection was thought to be a complication of the patient’s prior BCG therapy. He was initially started on isoniazid, rifampin, pyrazinamide and ethambutol pending cultures and sensitivities; pyrazinamide was discontinued after M. bovis was isolated on culture and susceptibility data confirmed the expected inherent resistance of M. bovis to pyrazinamide. The patient underwent successful THA revision and remains symptom-free at 1 year.

Background

Calmette and Guerin first developed the BCG vaccine in 1919 at the Pasteur Institute in Lille, France. It consists of M. bovis strain which is a member of the Mycobacterium tuberculosis (MTB) complex that also includes M. tuberculosis, M. africanum and M. microti. The live attenuated vaccine was first inoculated into humans in 1921.¹ Animal studies later demonstrated an immunomodulatory effect of BCG, reducing the rate of recurrence in various forms of cancer. In 1976, intravesical BCG was first introduced in the management of bladder cancer, and BCG remains part of the standard of care for treatment of high-risk non-muscle invasive bladder cancer.² It demonstrates a superior efficacy to transurethral resection (TUR) alone or TUR with chemotherapy and has been shown in randomised controlled trials to be the most effective agent in preventing recurrence compared with other immunotherapies.³

The complications associated with BCG intravesicular therapy are primarily localised to surrounding tissue, but there is an extensive list of severe systemic complications including granulomatous prostatitis, pneumonitis, hepatitis, osteomyelitis and infected orthopaedic or valvular prosthesis. While these are uncommon, there has been a growing recognition of the infectious complications of intravesicular BCG in the last decade. Therefore, the need for guidelines on management and prophylaxis has gained increased significance. We report a case of M. bovis prosthetic joint infection (PJI) of a left total hip arthroplasty (THA) after intravesical BCG therapy for bladder carcinoma. The patient was successfully treated with a two-stage hip revision and 1 year of antimycobacterial therapy. Other cases of M. bovis PJI with associated treatment and outcomes were also reviewed (table 1). To our knowledge, only 12 cases have been previously reported.

Table 1.

Summary of published case reports involving infection of joint arthroplasty and bladder cancer treatment with BCG.

Case report	Age (years)	Prior orthopaedic procedure	Treatment (antibiotic duration and surgical procedure)	Condition at follow-up
Leach and Halpin14	84	Right TKA	E and R with Girdlestone arthroplasty	Asymptomatic
Chazerain et al 15	77	Left TKA	Two-stage revision; I/R/E for 2 years	Asymptomatic at 2 years
Segal and Krauss16	76	Left THA	Two-stage revision; I/R/E for 1 year	Asymptomatic at 3 years
Gomez et al 17	82	Right THA	One-stage revision; I and R for 1 year	Asymptomatic at 1 year
Guerra et al 18	66	Right THA	Two-stage revision; I and R for 6 months	Died from unrelated causes prior to revision
Reigstad and Siewers19	86	Left THA	One-stage revision; I/R/P for 6 months; I/R for 6 months; I for 1 year	Asymptomatic at 2.5 years
Rispler et al 20	66	Left TKA	Arthroscopic I&D; implant retention; I/R for 1 year	Asymptomatic at 7.5 years
Nguyen et al 21	90	Left THA	Two stage revision; R/I/E for 1 year	Asymptomatic at 1 year
Aitchison et al 22	80	THA	Debridement and multiple washouts; I/R/E for 15 months	At 27 months there is a 3 mm sinus at hip wound; oral clindamycin 300 mg three times a day for suppression
Metayer et al 23	70	Left THA	One-stage revision; I/R/E for 1 year. Moxifloxacin stopped after 30 days
Srivastava et al 24	76	Right THA	Two stage revision; antituberculosis medications for nine months	Asymptomatic at 5 months
Williams et al 25	70	Left THA	One-stage revision; E for 3 months; moxifloxacin for 9 months; I/R for 12 months	Asymptomatic at 24 months
Present case	91	Left THA	Two-stage revision; I/R/E for 2 months; I/R for 10 months	Asymptomatic at 1 year

E, ethambutol; I, isoniazid; I&D, incision and drainage; P, pyrazinamide; R, rifampin; THA, total hip arthroplasty; TKA, total knee arthroplasty.

Case presentation

A 91-year-old man with osteoarthritis status post bilateral THA and bladder cancer presented to the Orthopaedics clinic complaining of left hip pain for 1 month. The patient had left THA 34 years ago with the most recent revision done 17 years prior to his current presentation. In addition, the patient underwent TUR 14 years ago for bladder cancer. The patient received three instillations of intravesicular BCG due to multiple recurrences of bladder cancer. His most recent course of BCG was 3 years ago and subsequent surveillance cystoscopies have been negative. It should be noted that the patient had no prior side effects to the instillations.

In the Orthopaedics clinic, the patient reported lateral left hip pain that was worse with activity. He denied fevers, chills, night sweats, weight loss, or generalised malaise. Physical examination was notable for a palpable fluid collection at the incision site of his left THA. White cell count (WBC) was 8.58×10⁹/L (normal 4.0–10.8×10⁹/L) with 79% neutrophils. Radiography of the left hip showed stable loosening of the left cemented hip revision and peri-hardware lucency at the cement bone interface.

Investigations

An aspiration of the fluid collection was performed with return of 40 cubic centimetres (cc) of cloudy fluid. The WBC from the aspirate was 2044 cells/mm³ with 84% polymorphonuclear neutrophils. Routine and fungal cultures demonstrated no growth. Of note, acid fast bacillus (AFB) cultures were not ordered. The patient was managed conservatively since there was no objective evidence of infection.

Four months later, the patient returned to the Orthopaedics clinic with persistent hip pain and re-accumulation of fluid. Radiography of the left hip remained unchanged. Given the recurrence of fluid and persistent pain, the decision was made to proceed with an elective explant of left THA and placement of an antibiotic spacer for a possible infected left hip prosthesis. Routine intraoperative cultures from the prosthesis were negative and the patient was discharged on 6 weeks of intravenous ceftriaxone for presumed culture-negative PJI. However, the patient was subsequently readmitted when the AFB culture returned positive.

Treatment

The patient was started on isoniazid, rifampin, pyrazinamide and ethambutol for possible MTB. An evaluation for pulmonary tuberculosis (TB) with a chest X-ray was unremarkable. AFB cultures from the left hip prosthesis ultimately grew MTB complex which was later identified as M. bovis. Therefore, we concluded that the PJI was a delayed complication from his intravesicular BCG treatment. M. bovis is intrinsically resistant to pyrazinamide so this was discontinued. The patient was treated with isoniazid, rifampin and ethambutol for 2 months followed by isoniazid and rifampin for 10 additional months based on previous case reports of M. bovis PJIs. Due to concern for prolonged immobility in an elderly patient, the decision was made to proceed with a left hip revision after only 2 months of antimycobacterial therapy.

Outcome and follow up

After 1 year of follow-up, the patient continues to improve without evidence of infection.

Discussion

Although generally well-tolerated, intravesicular BCG can cause local or systemic side effects. Instillation of BCG produces a local inflammatory response which is often manifested by urinary frequency (71%), cystitis (67%), fever (25%) and haematuria (23%).⁴ Serious or systemic side effects are rare. Lamm et al published a review of complications in 2602 patients treated with intravesicular BCG. The incidence of systemic BCG infection defined as pneumonitis or hepatitis was only 0.7%.^{5 6} However, in a more recent review of 256 patients treated with intravesicular BCG at a single centre, Asin et al ⁷ reported an incidence of systemic BCG infection of 4.3%.⁸ Disseminated and genitourinary were the most common sites of infection. Osteoarticular complications were rare in both studies and most often manifested by reactive arthritis rather than true infection.

The exact pathogenesis of systemic infection following instillation of intravesicular BCG is not fully understood. It is thought that local inflammation leads to disruption of the uroepithelial cells of the bladder thereby allowing organisms to disseminate haematogenously or via lymphatics.⁹ It has also been reported that BCG can persist in the bladder for more than a year after completion of intravesicular BCG instillation.¹⁰ Therefore, any cause of bladder inflammation may lead to dissemination of BCG long after the completion of therapy. In our patient, for example, he developed a BCG PJI approximately 2 years after BCG therapy. Of the cases reviewed, seven cases reported BCG PJI more than 18 months after therapy. It is also important to note that a majority of the patients in the reviewed cases lacked any systemic signs of infection such as fever or leukocytosis.

Treatment of BCG PJI is not well defined. As with other more common causes of PJI, management of BCG PJI generally consists of surgical intervention and a prolonged course of antimicrobial therapy. A four-drug regimen including isoniazid, rifampin, pyrazinamide and ethambutol should be initiated once a mycobacterial infection is identified. Since M. bovis is inherently resistant to pyrazinamide, the antimicrobial regimen can be de-escalated to two or three drugs after M. bovis is isolated. A total duration of at least 6 months is recommended. On review of the literature, the duration of antimicrobial therapy ranged from 6 to 24 months. There were no identified treatment failures.

Surgical management also varied considerably in the reviewed cases. Most patients were treated with a two-stage revision as with the management of PJI due to typical organisms. A two-stage revision includes explantation of the infected hardware and completion of antimicrobial therapy followed by re-implantation of the joint prosthesis. In cases of BCG PJI, this would lead to prolonged immobility as a minimum of 6 months of antimicrobial therapy is recommended. There is considerable morbidity associated with such prolonged immobility as the average age was 76.9 in the reviewed cases. This raises the question of whether BCG PJI can be treated with an alternative surgical approach. Unlike other bacterial infections of prosthetic joints, it appears that M. bovis does not produce biofilms and may be amenable to less aggressive surgical management.¹¹ Our patient, for example, was treated with a two-stage revision, but the hip was re-implanted after only 2 months of antimicrobial therapy due to concerns of prolonged immobility in an elderly patient. Four out of the 12 cases of BCG PJI identified in the literature were treated successfully with a one-stage revision. Rispler et al even reported success with a retained implant.

Given the significant morbidity associated with BCG PJI, there is considerable interest in determining whether prophylaxis is effective. The data on prophylaxis is quite limited, but there are case reports of systemic BCG infections despite using isoniazid prophylaxis.^{12 13} In addition, Asin et al performed a retrospective review to identify possible risk factors associated with disseminated BCG infection. They found no association between BCG infection and a variety of risk factors including age, gender, time from TUR, number of BCG instillations and previous active TB. However, the analysis included only 11 patients with BCG infections.

BCG PJI is a rare but significant complication of intravesicular BCG therapy. This case highlights the persistent risk of disseminated BCG infection even years after the completion of therapy. Physicians must therefore maintain a high index of suspicion for BCG PJI in patients with any history of bladder cancer treated with intravesicular BCG. In addition, the management of BCG PJI remains undefined. Further investigation is needed to determine the optimal surgical approach and duration of antimicrobial therapy.

Learning points.

• Complications associated with BCG intravesicular therapy are primarily localised to surrounding tissue, but there is an extensive list of severe systemic complications including granulomatous prostatitis, pneumonitis, hepatitis, osteomyelitis and infected orthopaedic or valvular prosthesis.

• The exact pathogenesis of systemic infection following instillation of intravesicular BCG is not fully understood but it has been reported that BCG can persist in the bladder for more than a year after completion of intravesicular BCG instillation.

• Treatment of BCG prosthetic joint infection is not well defined but management generally consists of surgical intervention and a prolonged course of antimicrobial therapy.