394 M bovis Vertebral Osteomyelitis From BCG Use Mayo Clin Proc, April 2002, Vol 77 Figure 1. Magnetic resonance imaging scan of the lumbar spine. Lef

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1 Mayo Clin Proc, April 2002, Vol 77 M bovis Vertebral Osteomyelitis From BCG Use 393 Case Report Mycobacterium bovis Vertebral Osteomyelitis as a Complication of Intravesical BCG Use RIMA ABU-NADER, MD, AND CHRISTINE L. TERRELL, MD We report a culture-proven case of Mycobacterium bovis vertebral osteomyelitis in a 76-year-old man who had undergone intravesical BCG therapy for bladder cancer 7 years previously. He presented with debilitating back pain and had radiographic evidence of T6-7 disk space destruction with involvement of adjacent vertebrae. Tissue culture from the disk space confirmed the diagnosis of vertebral osteomyelitis due to hematogenous spread of M bovis. Treatment with antituberculous medications was begun soon after tissue diagnosis was made, and the patient fared well with medical therapy alone. Although uncommon, this infectious complication of BCG therapy should always be considered in the appropriate clinical setting. Timely diagnosis is important, because chemotherapy, when initiated early in the disease, can preclude the necessity for surgical intervention. Mayo Clin Proc. 2002;77: With the implementation of intensive milk pasteurization programs in the last century, Mycobacterium bovis was becoming a forgotten pathogen, accounting for less than 0.1% of all mycobacterial isolates reported to the Centers for Disease Control and Prevention. 1 It regained public interest when bacillus Calmette-Guérin (BCG), an attenuated derivative of the virulent strain of M bovis, was approved as a vaccine and later as an anticancer agent in medical practice. Subsequently, a number of complications have arisen from broad-spectrum use of BCG. The incidence and type of complication associated with BCG vaccination or immunotherapy depend on the particular strain, dose, and route of administration. The risk of osteomyelitis of the long bones following BCG immunization is one in a million; the spine is involved even less commonly. 2 The incidence of hematogenous dissemination to bone following intravesical BCG therapy for bladder cancer is even more rare, with only a few cases reported in the English-language literature. Herein, we describe a case of vertebral osteomyelitis presenting 7 years after intravesical BCG treatment for transitional cell bladder carcinoma. REPORT OF A CASE A 76-year-old man was referred to our institution in July 1998 for management of chronic, unrelenting back pain. He first noticed the onset of mid to lower back pain 6 From the Division of Infectious Diseases, University of Iowa Hospitals and Clinics, Iowa City (R.A.-N.); and Division of Infectious Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn (C.L.T.). Individual reprints of this article are not available. Address correspondence to Christine L. Terrell, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN ( terrell.christine@mayo.edu). months before initial medical evaluation. Pain radiated to his left chest wall and was associated with anorexia and an 11.4-kg weight loss. He denied fever, chills, cough, night sweats, motor or sensory deficits, and changes in bladder or bowel function. As far as he could remember, he had not sustained any major falls or other types of trauma before the onset of his symptoms. His medical history was contributory for squamous cell carcinoma of the left upper lung (T2 N0 M0) that was surgically resected in 1992, psoriasis, degenerative spondylosis of the cervical spine, and benign prostatic hyperplasia. He also had bladder cancer diagnosed in 1991, for which he received 6 weekly cycles of intravesical BCG instillations. The results of follow-up cystoscopic examinations were negative for tumor recurrence, with the most recent examination performed a month previously, and the patient reported no adverse effects from BCG therapy. He admitted heavy cigarette smoking and a remote exposure to tuberculosis but did not recall prior tuberculin skin testing. He had never received the BCG vaccine and denied any drug allergies. During the ensuing months, he developed lower extremity weakness and paresthesias and began a dual regimen of high-dose corticosteroids and narcotics. A magnetic resonance imaging scan confirmed the presence of a destructive process involving the T6-7 disk interspace and adjacent vertebral bodies (Figure 1). A presumptive diagnosis of metastatic lung cancer was made, and the patient underwent empiric radiation therapy to the back and chest. Despite a complete course of radiation and ongoing steroid and narcotic support, the patient s symptoms continued to worsen, and he presented to our clinic 5 months later for further evaluation. At that time, he was still taking dexamethasone, 4 mg twice daily (slow taper from 12 mg twice daily), and oxycodone hydrochloride, 20 mg twice daily. Mayo Clin Proc. 2002;77: Mayo Foundation for Medical Education and Research

2 394 M bovis Vertebral Osteomyelitis From BCG Use Mayo Clin Proc, April 2002, Vol 77 Figure 1. Magnetic resonance imaging scan of the lumbar spine. Left, T1-weighted image demonstrates a destructive lesion of the T6 and T7 vertebrae and intervening disk (arrow) with associated marked disk space narrowing and loss of contiguous end plates. Middle, T1-weighted image obtained with gadolinium contrast reveals enhancement within the involved vertebrae and disk space (arrow). Right, T2-weighted image demonstrates increased signal in the inferior and superior portions of the thoracic vertebral bodies T6 and T7 (arrow), respectively. On physical examination, vital signs were normal. The back was mildly kyphotic with mild percussion tenderness over the spinous processes of the thoracic vertebrae. Reflexes were brisk at the knees, and there was mild motor weakness and pitting edema of the lower extremities. Initial laboratory data showed mild normochromic normocytic anemia, a normal leukocyte count, and an erythrocyte sedimentation rate of 10 mm/1 h. Renal and liver function test results were unremarkable. A tuberculin skin test result was negative. A chest radiograph revealed thoracotomy changes with elevation of the left hemidiaphragm. A computed tomography guided needle biopsy of the involved disk space was performed and 4 weeks later yielded a positive culture for mycobacteria. The patient initially began therapy with a 4-drug regimen of isoniazid, rifampin, ethambutol, and pyrazinamide. By using DNA probes, the isolate was preliminarily reported to be a member of the Mycobacterium tuberculosis complex; it was subsequently identified as M bovis. When susceptibility testing showed that the isolate was susceptible to isoniazid, rifampin, ethambutol, and streptomycin, but resistant to pyrazinamide (minimum inhibitory concentration >100), the regimen was changed to a 12-month course of isoniazid, rifampin, and ethambutol. He did not require surgical intervention for thoracolumbar stabilization based on lack of spinal cord compression or instability, and his symptoms were markedly improved on subsequent follow-up. DISCUSSION The introduction of intravesical BCG immunotherapy in the treatment of superficial bladder cancer in the 1970s was a major breakthrough and appeared to carry a low risk for adverse effects, most of which were localized and selflimited. 3 At the turn of the 21st century, BCG immunotherapy continues to play a major role in reducing recurrence rate and prolonging disease-free survival after surgical resection of cancer of the bladder. Furthermore, BCG has become the initial treatment of choice for carcinoma in situ. 4 The standard induction schedule consists of 6 weekly instillations into the bladder to be held for 2 hours each time. 3 Prior experience with BCG had been obtained from tuberculosis immunization campaigns that were carried out in many countries worldwide since A live attenuated strain of M bovis, a member of the M tuberculosis complex, which includes M tuberculosis, Mycobacterium africanum, and Mycobacterium microti, was used in the vaccine preparations. It was shown to have some efficacy in preventing active tuberculosis and was thought to have a good safety profile. 6 Adverse reactions have been mainly limited to suppurative lymphadenitis and/or localized abscess formation.

3 Mayo Clin Proc, April 2002, Vol 77 M bovis Vertebral Osteomyelitis From BCG Use 395 However, cumulative data from decades of research have revealed rare but serious complications with the vaccine. 6,7 BCG osteomyelitis that affects children, as early as 5 months to 5 years after immunization, was reported in Europe, with an estimated incidence of 1 per 80,000 vaccinated children. 8 The Scandinavian experience with BCG vaccine was reviewed from 1961 to ; 18 cases of BCG osteitis were diagnosed among vaccinated children, with a mean annual frequency of 1 in 17,000 vaccinated children. The higher incidence observed in Scandinavian countries was ascribed to the injection technique, dose, and strain used. As the application of BCG intravesical immunotherapy increased after it was first used successfully in 1976, 3 the spectrum of potential complications became clearer. The largest series was a retrospective study by Lamm et al 10 involving 2602 patients. Although adverse effects such as cystitis (>90%), fever (2.9%), hematuria (1%), prostatitis (0.9%), and arthralgias or arthritis (0.5%) were relatively common, extravesical complications were rare. Other local adverse effects included bladder contractures, epididymoorchitis, ureteral obstruction, and renal abscesses with or without fistula formation. Of note, among the various BCG preparations used in this large series, there were no significant differences in the complication rates observed. Granulomatous involvement of various organs, such as lung (pneumonitis), liver (hepatitis), 13 kidney, 14 and bone marrow (cytopenia), 10,13 is sometimes seen in association with BCG immunotherapy. A combined incidence of pneumonitis and hepatitis occurred in 1% of patients in this retrospective series. There has been an ongoing debate regarding the underlying mechanism of systemic manifestations related to BCG therapy or vaccination. It appears that both direct infectious processes and hypersensitivity reactions contribute to the clinical manifestations of a systemic BCG infection. A granulomatous response may occur with either an infectious or a hypersensitivity mechanism and is not pathognomonic for disseminated infection. However, the finding of a positive culture of mycobacteria from a distant site is a direct indication of dissemination. Scattered reports of culture-proven M bovis BCG dissemination with or without evidence of trauma to the bladder or immunocompromise have accrued in the literature. 7 Furthermore, 8 cases of mycotic vascular infections of large arteries after BCG intravesical therapy have been confirmed. 15 Other metastatic complications, such as infection of implantable devices 16 or prosthetic joints 17 and psoas abscesses, 18,19 have been attributed to BCG dissemination following intravesical administration. Fatal reactions from BCG occasionally occur; the highest fatality rate is seen with intralesional therapy of highly vascularized tumors 20 and in patients with immune deficiencies. 6 A recent description of a genetic deletion in the gene encoding the interferon γ or interleukin 12 receptor and their clinical consequences is noteworthy. These specific defects impair the host s defense against mycobacterial infections, including the BCG vaccine Although it is remotely possible that, in the patient we describe, the M bovis was acquired from another source, the rarity of the organism and known association with bladder instillation would strongly argue against this possibility. To date, only 7 other cases of intravesical BCGrelated vertebral osteomyelitis have been reported in the English-language literature (Table 1). The first case report of BCG osteomyelitis and psoas abscess following intravesical BCG therapy was published in A tuberculin skin test is not very helpful in the diagnostic work-up of M tuberculosis complex disease, because most of these patients are elderly and demonstrate anergy to the skin test (Table 2). Recently, diagnostic testing by a rapid molecular method that differentiates M bovis BCG from its parent M bovis strain has been developed. 31 Methods for further identification of BCG strains include phage typing, 32 highperformance liquid chromatography, 28,33 and restriction fragment length polymorphism analysis. 34 The pathogenesis of vertebral osteomyelitis secondary to intravesical BCG therapy may be the result of hematogenous spread to the anterior vertebral bodies of the spine where the arterial supply converges. There is a predilection for thoracolumbar involvement with a high incidence of disease occurring in the lower thoracic vertebrae. The radiographic appearance of early lesions includes loss of margin of the vertebral end plates and narrowing of the disk space. 28,35,36 A number of risk factors have been associated with an increased incidence of serious complications from BCG intravesical therapy and include trauma to the bladder epithelium from catheterization, deep bladder tumor resection or urethral injury during BCG instillation, bladder outlet obstruction, pelvic radiation, other forms of severe cystitis, and immunocompromised state. 12,13,18,29 Transurethral resection of the prostate or bladder biopsy within 2 weeks before BCG instillation also predispose the patient to complications. 37 It is postulated that these factors facilitate the hematogenous spread of viable M bovis bacilli but are not prerequisites for dissemination as consistently shown in animal model data. 38 Bacilli of BCG origin have been demonstrated in bladder biopsy specimens and early-morning urine cultures for more than a year following completion of intravesical therapy. 39 This prolonged persistence of viable bacilli may explain why patients are still at risk of disseminated infection even months and perhaps years after the introduction of BCG. It is plausible that in our case the patient s vertebral seeding with M bovis became manifest or recrudesced in the setting of corticosteroids and recent cystoscopy.

4 396 M bovis Vertebral Osteomyelitis From BCG Use Mayo Clin Proc, April 2002, Vol 77 Table 1. A Summary of Reported Cases of BCG Therapy Related Skeletal Complications Patient Time age Site of of Antimicrobial therapy Reference (y)* Dose/route/BCG strain infection onset Diagnosis and culture and outcome Strausser & organisms/ Vertebral 3 y Caseating granulomas and Isoniazid, rifampin, and etham- Quindlen, 27 intralesional/not specified positive acid-fast bacillus butol; no long-term follow-up 1981 stains; negative surgical reported cultures Katz et al, mg/mo for 12 mo/ Vertebral 16 mo Positive tissue biopsy Isoniazid and rifampin; 1992 intravesical/connaught or psoas cultures for M bovis discharged after 2 mo abscess Fishman 90 Weekly instillation for 6 wk/ Vertebral 4 wk Open surgical biopsy; culture Isoniazid, rifampin, and ethamet al, intravesical/japanese positive for M bovis butol (patient received isoniazid prophylaxis for previous 6 wk); not specified Civen et al, One instillation per week for 6 Vertebral 7 mo Open surgical biopsy; blood Isoniazid and rifampin for 1994 wk, then 1 per month for 2 cultures positive for 1 y; alive 1 y later mo/intravesical/not specified M bovis Morgan & 77 2 cycles (6 treatments/cycle)/ Vertebral 2 wk Needle biopsy; culture Isoniazid, rifampin, and etham- Iseman, 30 intravesical/not specified positive for M bovis butol for 6 mo, then isoniazid 1996 and rifampin for 6 mo; alive 1 y later Guerra et al, mg/wk for 12 wk/ Hip 20 mo Positive surgical culture for Isoniazid and rifampin; died of 1998 intravesical/tice arthroplasty M bovis lung cancer 3 y later Aljada et al, 5 79 One instillation per week for Vertebral 2.5 y Surgical tissue cultures Isoniazid and rifampin for wk/intravesical/tice positive for M bovis 12 mo; alive 1 y later *All patients were male. After BCG therapy. In this case report, there was a history of recent trauma and presumed locus minoris resistentiae effect. Unlike M tuberculosis, all strains of M bovis are intrinsically resistant to pyrazinamide. Hence, other drugs in the armamentarium, namely, isoniazid and rifampin, with or without ethambutol, should be used as first-line agents. 14,20 Common local adverse effects, such as cystitis, hematuria, and systemic low-grade fever, may be treated symptomatically. Here, isoniazid prophylaxis has not been proven to be effective in reducing their frequency. Treatment with isoniazid or rifampin with or without ethambutol must be initiated, however, and subsequent BCG instillations halted if granulomatous prostatitis, epididymitis, or ureterorenal complications were to occur. In the case of disseminated systemic infection or specific organ involvement as in our case report of vertebral osteomyelitis, triple antimycobacte- rial therapy is warranted and corticosteroids may be added as an adjunctive treatment. 40 Surgical intervention was necessary in 5 of the 6 reported cases of vertebral osteomyelitis for spine stabilization and/or abscess drainage. CONCLUSION As this case report demonstrates, intravesical BCG therapy may be complicated by disseminated disease to the bone even years after treatment has been completed. Predisposing factors to dissemination should be addressed before initiation of BCG therapy to minimize the risk of hematogenous spread of live attenuated mycobacteria to distant sites. A high index of suspicion of BCG-related osteomyelitis is paramount in the appropriate clinical setting, and Table 2. Results of Tuberculin Testing in Case Reports of BCG Therapy Related Bone and Joint Infections Reference Infection Test result Strausser & Quindlen, Intralesional BCG for melanoma, vertebral osteomyelitis Conversion in 1 y Katz et al, Intravesical BCG for bladder cancer, vertebral osteomyelitis and psoas abscess Unknown Fishman et al, Intravesical BCG for bladder cancer, vertebral osteomyelitis Anergy Civen et al, Intravesical BCG for bladder cancer, vertebral osteomyelitis Negative Morgan & Iseman, Intravesical BCG for bladder cancer, vertebral osteomyelitis Unknown Guerra et al, Intravesical BCG for bladder cancer, prosthetic hip joint infection Anergy Aljada et al, Intravesical BCG for bladder cancer, vertebral osteomyelitis Unknown

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