Bacillus Calmette-Guérin (BCG) Infection Following Intravesical BCG Administration as Adjunctive Therapy For Bladder Cancer

Bacillus Calmette-Gu erin (BCG) is the most effective intravesical immunotherapy for superficial bladder cancer. Although generally well tolerated, BCG-related infectious complications may occur following instillation. Much of the current knowledge about this complication comes from single case reports, with heterogeneous diagnostic and therapeutic approaches and no investigation on risk factors for its occurrence. We retrospectively analyzed 256 patients treated with intravesical BCG in our institution during a 6-year period, with a minimum follow-up of 6 months after the last instillation. We also conducted a comprehensive review and pooled analysis of additional cases reported in the literature since 1975. Eleven patients (4.3%) developed systemic BCG infection in our institution, with miliary tuberculosis as the most common form (6 cases). A 3-drug antituberculosis regimen was initiated in all but 1 patient, with a favorable outcome in 9/10 cases. There were no significant differences in the mean number of transurethral resections prior to the first instillation, the time interval between both procedures, the overall mean number of instillations, or the presence of underlying immunosuppression between patients with or without BCG infection. We included 282 patients in the pooled analysis (271 from the literature and 11 from our institution). Disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections were the most common presentations of disease. Specimens for microbiologic diagnosis were obtained in 87.2% of cases, and the diagnostic performances for acid-fast staining, conventional culture, and polymerase chain reaction (PCR)-based assays were 25.3%, 40.9%, and 41.8%, respectively. Most patients (82.5%) received antituberculosis therapy for a median of 6.0 (interquartile range: 4.0–9.0) months. Patients with disseminated infection more commonly received antituberculosis therapy and adjuvant corticosteroids, whereas those with reactive arthritis were frequently treated only with nonsteroidal antiinflammatory drugs (p< 0.001 for all comparisons). Attributable mortality was higher for patients aged 365 years (7.4% vs 2.1%; p 1⁄4 0.091) and those with disseminated infection (9.9% vs 3.0%; p1⁄4 0.040) and vascular involvement (16.7% vs 4.6%; p1⁄4 0.064). The scheduled BCG regimen was resumed in only 2 of 36 patients with available data (5.6%), with an uneventful outcome. In the absence of an apparent predictor of the development of disseminated BCG infection after intravesical therapy, and considering the protean variety of clinical manifestations, it is essential to keep a high index of suspicion to initiate adequate therapy promptly and to evaluate carefully the risk-benefit balance of resuming intravesical BCG immunotherapy. (Medicine 2014;93: 236–254) Abbreviations: ALP = alkaline phosphatase, BCG = bacillus Calmette-Gu erin, COPD = chronic obstructive pulmonary disease, CT = computerized tomography, EMB = ethambutol, ESRD = end-stage renal disease, GGT = gamma-glutamyl transpeptidase, HIV = human immunodeficiency virus, HLA = human leukocyte antigen, INH = isoniazid, IS = immunosuppression, LEV = levofloxacin, NR = not reported, NSAID = nonsteroidal antiinflammatory drug, PCR = polymerase chain reaction, PPD = purified protein derivative, PZA = pyrazinamide, RCT = randomized clinical trial, RIF = rifampicin, SD = standard deviation, TB = tuberculosis, TST = tuberculin skin test, TUR = transurethral resection. INTRODUCTION The intravesical administration of bacillus Calmette-Gu erin (BCG), an attenuated live strain of Mycobacterium bovis, has become a mainstay of adjunctive therapy for superficial bladder cancer. Although usually well tolerated, both local and systemic BCG-related complications may occur following instillation. While these events are uncommon, with a cumulative incidence lower than 5%, its wide From the Unit of Infectious Diseases (MAPJA, MFR, FLM, CL, RSJ, ML, JMA), Department of Urology (AT, AAP), and Department of Internal Medicine (SP), Hospital Universitario “12 de Octubre,” Instituto de Investigaci on Hospital “12 de Octubre” (i+12), Madrid, Spain. Correspondence: Mar ıa Asunci on P erez-Jacoiste As ın, MD, Unit of Infectious Diseases, Hospital Universitario “12 de Octubre,” Centro de Actividades Ambulatorias, 2a planta, bloque D. Avda. de C ordoba, s/n. Postal code 28041, Madrid, Spain (e-mail: mperezja82@ hotmail.com). This study was partially presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (poster P-2387), Berlin, April 27-30, 2013. Funding and conflicts of interest: Mario Fern andez-Ruiz holds a research-training contract “Rio Hortega” (CM11/00187) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III. Francisco L opez-Medrano is partially supported by a grant from the Research Intensification Program in the National Health Care System (I3SNS) from the Spanish Ministry of Economy and Competitiveness (Instituto de Salud Carlos III). For the remaining authors, no funding sources or conflicts of interest. Copyright © 2014 by Lippincott Williams & Wilkins. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000119 236 | www.md-journal.com Medicine • Volume 93, Number 17, October 2014 range of presentations and potential severity poses a challenge for the clinician. However, much of our knowledge on the infectious complications related to intravesical BCG therapy comes from individual case reports, thus hampering a comprehensive understanding of this entity. The pathogenic mechanisms underlying the development of complications following BCG instillation remain not fully understood, and considerable debate exists about whether it represents a form of hypersensitivity reaction—on the basis of the histologic finding of granulomas in the absence of recoverable microorganisms—or an active mycobacterial infection—since some authors have demonstrated viable bacilli in a variety of tissues. In addition, the predisposing factors for developing an intravesical BCG-related complication are not well known. It has been suggested that some conditions may result in the hematogenous dissemination of the bacilli (that is, disruption of the urothelial barrier due to traumatic urinary catheterization, early instillation after transurethral resection [TUR] of bladder cancer, or concurrent urinary tract infection), but there are still limited data on other potential risk factors, namely the presence of underlying immunosuppression. In the present study we aimed at analyzing a large cohort of patients who underwent intravesical BCG instillation in our institution during a 6-year period in order to determine the incidence, risk factors, and outcome of systemic BCG infection. An exhaustive review and pooled analysis of the cases of BCG infection following intravesical immunotherapy reported in the literature since 1975 is also presented, with particular focus on the nature of complication (local or systemic), therapeutic approach, and outcome. PATIENTS AND METHODS Study Setting and Data Collection This study was performed at the University Hospital “12 de Octubre” (Madrid, Spain), a 1300-bed tertiary care center with a reference population that ranged from 536,450 to 405,577 inhabitants during the study inclusion period (December 31, 2003, to October 31, 2009). By means of a retrospective search of the institutional database we identified a total of 315 patients who received 31 instillations of intravesical BCG (Connaught strain, 81mg in 50mL of sterile saline) as adjunctive treatment of superficial bladder cancer throughout this period. We excluded 59 patients (18.7%) due to the lack of clinical data, so 256 patients were finally included. All the patients were followed for at least 6 months after the last intravesical instillation. The need for specific informed consent was waived by the institutional review board due to the strictly retrospective and noninterventional nature of the investigation. The following variables were retrospectively assessed by medical record review using a standardized data collection form: demographics; number of TURs prior to the first BCG instillation; overall number of BCG instillations; time interval between the last TUR and the first instillation; prior history of tuberculin skin test (TST) or active tuberculosis disease; alcohol and smoking habits; comorbid conditions; and immunosuppression. We recorded the total leukocyte and lymphocyte counts just before the first instillation as a proxy for the patient’s immune status. A number of additional variables were also recorded for those patients who developed systemic BCG infection (as defined below): time interval between the first BCG instillation and the diagnosis of the complication; type of infection; presence of miliary pattern on chest imaging studies (simple radiography or computerized tomography [CT] scan); histologic and microbiologic findings; treatment; and outcome. One of these cases has been previously published. Definitions Used in the Institutional Cohort Study Systemic BCG infection was defined by the presence of miliary tuberculosis (clinical presentation consistent with active tuberculosis associated to a typical miliary pattern on chest imaging), hepatitis, nephritis, lymphocytic meningitis, arthritis, or osteomyelitis, following 31 instillations of intravesical BCG, responding to antituberculosis treatment, and with no alternative diagnosis. Microbiologic (positivity for Mycobacterium tuberculosis complex by culture or by polymerase chain reaction [PCR] assay) and/or histopathologic evidence of mycobacterial infection (that is, caseating granulomas in biopsy specimens) were not deemed necessary for diagnosis. We also included in such definition the occurrence, within the first 4 hours after BCG instillation, of persistent fever (338°C for more than 72 h) and night sweating, with rapid defervescence after initiation of antituberculosis treatment, and no alternative clinical cause or microbiologic documentation (other than the isolation of M. bovis in urine samples). Immunosuppression was defined by the presence of 31 of the following conditions: long-term corticosteroid therapy (35mg daily of prednisone or equivalent for >2 wk), use of other immunosuppressive or cytostatic agents within the previous 6 months, advanced human immunodeficiency virus (HIV) infection (CD4+ T-cell count 0.200 10 cells/μL), neutropenia (absolute neutrophil count 0.500 10 cells/μL), other primary or secondary immunodeficiencies, and asplenia. Literature Review and Pooled Analysis of Cases We conducted a computer-based MEDLINE (National Library of Medicine, Bethesda, MD) search with the terms “intravesical instillation” and “bacillus Calmette-Gu erin” and “BCG infection” or “tuberculosis, miliary” or “complications” to identify literature pertaining to the subject published between January 1975 and April 2013. Overall, we retrieved 390 articles (including case reports, case series, review articles, and randomized clinical trials [RCTs]). First, we excluded papers in languages other than English, French, Spanish, Italian, or Portuguese (28 articles). After a detailed evaluation, we also excluded those papers that clearly referred to other subjects, which overall added up to 137 (antitumor mechanism of BCG [26 articles], efficacy of intravesical BCG as treatment for bladder cancer [38 articles], comparative analyses of different doses and strains of BCG [4 articles], alternative treatments for superficial bladder cancer [12 articles], comparative analyses between BCG and other intravesical agents [10 articles], alternative routes for the administration of BCG [9 articles], detection of M. bovis in asymptomatic patients after receiving intravesical BCG [10 articles], and potential efficacy of isoniazid [INH] or quinolones for prevention of BCG complications [3 articles], among others). We excluded the case previously reported from our institution, which had been included into our cohort study. We also excluded 9 literature reviews with no original data, 7 studies based on animal models, 4 guidelines, 1 article based ã 2014 Lippincott Williams & Wilkins www.md-journal.com | 237 Medicine • Volume 93, Number 17, October 2014 BCG Infection After BCG Intravesical Instillation