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  Table of Contents  
Year : 2014  |  Volume : 32  |  Issue : 4  |  Page : 438-439

Disseminated Bacillus Calmette-Guerin infections after intravesical therapy

1 Department of Respiratory Medicine, University Hospital of Larissa, Greece
2 Department of Urology, University Hospital of Larissa, Greece
3 Department of Microbiology, University Hospital of Larissa, Greece

Date of Submission22-Jul-2013
Date of Acceptance07-Feb-2014
Date of Web Publication4-Oct-2014

Correspondence Address:
E Petinaki
Department of Microbiology, University Hospital of Larissa
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0255-0857.142254

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 ~ Abstract 

Intravesical instillation of Bacillus Calmette-Guerin (BCG) is the treatment of choice for superficial bladder carcinoma. Disseminated BCG infection presenting as granulomatous hepatitis or pneumonitis is a very rare complication of this treatment. Here we report a case series of seven patients previously treated with BCG presenting with pneumonitis. In two of the cases, identification of Mycobacterium bovis was achieved with molecular methods.

Keywords: BCG, bladder carcinoma, Greece, tuberculosis

How to cite this article:
Gerogianni I, Gravas S, Gourgoulianis K, Neonakis I, Petinaki E. Disseminated Bacillus Calmette-Guerin infections after intravesical therapy . Indian J Med Microbiol 2014;32:438-9

How to cite this URL:
Gerogianni I, Gravas S, Gourgoulianis K, Neonakis I, Petinaki E. Disseminated Bacillus Calmette-Guerin infections after intravesical therapy . Indian J Med Microbiol [serial online] 2014 [cited 2020 Nov 23];32:438-9. Available from:

 ~ Introduction Top

Bacillus Calmette-Guerin (BCG) is a live, attenuated form of wild-type Mycobacterium bovis and has been used for vaccination against human tuberculosis. Since 1976, it has also been used for the treatment of superficial bladder cancer, and approved for the treatment of carcinoma in situ. [1],[2] It is believed to exert its anti-tumour activity via local modulation of immune responses, which results in inflammation and subsequent elimination of malignant cells. The most widely used regimen consists of a weekly intravesical BCG injection for 6 weeks, which is repeated three more times every 6 months. More than 95% of patients who receive BCG tolerate the treatment well. [3] Apart from minor reactions such as dysuria, frequency and cystitis, which are common, serious adverse events are rare. They may include high fever that usually resolves within 1-2 days, allergic reactions, granoulomatous Prostatitis or epididymo-orchitis and the most dangerous of all, BCG sepsis. [4] Sepsis is attributed to traumatic catheterisation and absorption of BCG by patients that have recently undergone tumour resection. Sepsis can be fatal and the rate is estimated to 1 death every 12,500 patients treated for cancer. [3] Disseminated BCG infections after intravesical instillations are presenting as granulomatous hepatitis or pneumonitis and are very rare. [5],[6],[7],[8],[9] Rarer is the identification of M. bovis as the causative agent of these disseminated infections, feasible only with molecular techniques. [10] Here we present seven cases of pneumonitis after intravesical BCG therapy and the identification of M. bovis in two of these cases.

Over the past 2 years, seven patients previously treated with intravesical BCG therapy for superficial bladder cancer were admitted to our hospital with the predominant symptom of fever. All patients were men, with a mean age of 75 ± 5 years, and mean duration of therapy of 12 ± 4 months. No prophylactic isoniazid had been given during their BCG instillation treatment. None of the patients had acquired immunodeficiency syndrome (AIDS) or any other immune deficiency by the time of admission. Other symptoms reported were night sweats, weight loss, dyspnoea and cough. All baseline blood and sputum cultures for common bacteria were negative. Their chest X-ray demonstrated bilateral interstitial opacities and furthermore non-contrast chest computed tomography scan performed on all patients illustrated bilateral parenchymal nodules in a miliary pattern without mediastinal adenopathy [Figure 1]a and b.
Figure 1

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A sputum sample for acid-fast staining and mycobacterial culture was obtained from each patient. Furthermore, bronchoscopy was assessed in all the patients. Transbronchial biopsies and bronchoalveolar lavage (BAL) samples were obtained for histopathology, acid-fast staining and mycobacterial cultures. All samples were treated according to standard procedures. [11] Lowenstein-Jensen slants (bioMérieux, Marcy l' Etoile, France) were used for solid cultures and the BACTET MGIT 960 Automated System (Becton Dickinson Biosciences, Sparks, Md.) was used for liquid cultures and susceptibility testing at 37°C. Acid-fast staining was negative for all samples. All BAL and biopsy mycobacterial cultures were also negative. However, to our surprise, two sputum mycobacterial cultures became positive. The isolates were identified as members of the M. tuberculosis complex with gene probes [AccuProbe (GenProbe, San-Diego, USA)]. Identification to the species level was achieved with GenoType MTBC (Hain Lifescience, Nehren, Germany), which is DNA-strip assay for differentiating M. tuberculosis complex strains. The procedure involves isolation of DNA from cultured material, multiplex amplification with biotinylated primers and reverse hybridisation of the single-stranded, biotin-labelled amplicons to membrane-bound probes. [12] The assay was performed according to the manufacturer's instructions, using the reagents provided and Taq DNA polymerase (Qiagen, Hilden, Germany). Both isolates were identified as M. bovis BCG. The isolates were sensitive to isoniazid, rifampin, streptomycin and ethambutol and, as anticipated, resistant to pyrazinamide. Histopathology showed that four of the seven biopsies (including those from the two patients with positive sputum cultures) had non-caseating granulomas indicative of mycobacterial infection. All patients were treated with cessation of BCG and triple anti-mycobacterial therapy consisting of rifampin, isoniazid and ethambutol for the first 3 months and isoniazid, rifampin for 7 months. All seven patients had clinical improvement on this regimen, supporting the clinical diagnosis.

Despite the fact that disseminated M. bovis infection is a very rare complication of intravesical BCG therapy, clinicians should always include it in their differential diagnosis list when treating patients undergoing such therapy. It is a dangerous yet treatable disease. Isolation and identification of M. bovis is uncommon and requires molecular methods. Upon clinical suspicion the BCG therapy should be ceased and appropriate anti-mycobacterial regimen should be administered as soon as possible.

 ~ References Top

1.Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180-3.  Back to cited text no. 1
2.Gandhi NM, Morales A, Lamm DL. Bacillus Calmette-Guérin immunotherapy for genitourinary cancer. BJU Int 2013;112:288-97.  Back to cited text no. 2
3.Koya MP, Simon MA, Soloway MS. Complications of intravesical therapy for urothelial cancer of the bladder. Urol 2006;175:2004-10.  Back to cited text no. 3
4.Lamm DL, van der Meijden PM, Morales A, Brosman SA, Catalona WJ, Herr HW, et al. Incidence and treatment of complications of Bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596-600.  Back to cited text no. 4
5.Kathman D, Oliveira P. Disseminated Bacillus Calmette-Guérin (BCG) infection as a consequence of immunotherapy for bladder carcinoma. Chest 2012;142:156A.  Back to cited text no. 5
6.Dammert P, Boujaoude Z, Rafferty W, Kass J. Fever of unknown origin and pancytopenia caused by culture-proven delayed onset disseminated Bacillus Calmette-Guerin (BCG) infection after intravesical instillation. BMJ Case Rep 2013;2013.  Back to cited text no. 6
7.Colmenero JD, Sanjuan-Jimenez R, Ramos B, Morata P. Miliary pulmonary tuberculosis following intravesical BCG therapy: Case report and literature review. Diagn Microbiol Infect Dis 2012;74:70-2.  Back to cited text no. 7
8.Lamm DL, Stogdill VD, Stogdill BJ, Crispen RG. Complications of Bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J Urol 1986;135:272-4.  Back to cited text no. 8
9.Gao CQ, Mithani R, Leya J, Dawravoo L, Bhatia A, Antoine J, et al. Granulomatous hepatitis, choroiditis and aortoduodenal fistula complicating intravesical Bacillus Calmette-Guérin therapy: Case report. BMC Infect Dis 2011;11:260.  Back to cited text no. 9
10.Neonakis IK, Gitti Z, Krambovitis E, Spandidos DA. Molecular diagnostic tools in mycobacteriology. J Microbiol Methods 2008;75:1-11.  Back to cited text no. 10
11.Koneman E, Allen S, Janda W, Schreckenberger P, Winn W. Color atlas and textbook of Diagnostic Microbiology. Philadelphia: Lippincott; 1997. 5th ed.  Back to cited text no. 11
12.Neonakis IK, Gitti Z, Petinaki E, Maraki S, Spandidos DA. Evaluation of the GenoType MTBC assay for differentiating 120 clinical Mycobacterium tuberculosis complex isolates. Eur J Clin Microbiol Infect Dis 2007;26:151-2.  Back to cited text no. 12


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