Cover: Urogenital Infections and Inflammations

Urogenital Infections and Inflammations

T.E. Bjerklund Johansen, F. M.E. Wagenlehner, Y.-H. Cho, T. Matsumoto, J. N. Krieger, D. Shoskes, K. Naber


BCG infections

 Tae-Hyoung Kim 1


1 Urology, Chung-Ang University, Seoul, South Korea

Abstract

Bladder cancer is commonly presented as a highly recurring superficial form. Following endoscopic resection, current practice recommends repeated intravesical instillation of the attenuated Bacillus Calmette-Guerin (BCG). BCG instillations are generally safe, with irritative voiding symptoms and flu like symptoms indicating treatment effect. However, less than 5% have presented with complications both localized and systemic. Early complications are generally systemic in nature, with low yield of microbiological diagnosis, whereas later complications tend to show granulomatous lesions, appearing later than 1 year or more since instillation. These complications are generally successfully managed with RIF, INH, and EMB, following treatment guidelines for tuberculosis. However, miliary tuberculosis may occur, requiring corticosteroid use and intensive care. Localized sites, with granulomatous mass lesions obstructing the genitourinary tract may require surgical management. The overall outcome is positive, however, in cases of vascular involvement high mortality may ensue.


List of Abbreviations

BCG – Bacillus Calmette-Guérin
EMB – Ethambutol
GoR – Grade of Recommendation
INH – Isoniazid
LoE – Level of Evidence
PCR – Polymerase Chain Reaction
PZA – Pyrazinamid
RIF – Rifampicin
TUR – Transurethral Resection
UTI – Urinary Tract Infection


Summary of recommendations

  1. Irritative voiding symptoms and flu-like symptoms within 24–48 hours following intravesical BCG instillation is an expected inflammatory reaction (GoR B). Following this period, patients presenting with genitourinary or systemic symptoms should be suspected of BCG infection after excluding alternative diagnoses (GoR B).
  2. Microbiologic diagnosis and/or histologic confirmation is recommended, but accompanies a high false negative rate, and clinical judgement with high suspicion based on history of previous BCG instillation is necessary (GoR C).
  3. Local or systemic complications are treated with INH, RIF, and EMB for 2 months, followed by INH and RIF for 4 months. PZA is not recommended (GoR C).
  4. In case of extensive systemic involvement, such as miliary tuberculosis, consider corticosteroid adjuvant therapy (GoR C).
  5. In the presence of abscess, and/or genitourinary mass lesions, consider surgical treatment (GoR C).

1 Introduction

Bladder cancer most commonly presents as a superficial type, amenable to endoscopic surgery. However, approximately 90% of these patients will develop tumor recurrence. Since Morales et al. first introduced intravesical instillation of Bacillus Calmette-Guerin (BCG) to treat superficial bladder cancer in 1976, it has shown wide success, eradicating residual tumors in more than 60% of patients with papillary carcinoma and 70% of patients with carcinoma in situ [1].

Intravesical instillation of BCG utilizes the live attenuated strain of Mycobacterium bovis and has since become a mainstay adjunctive therapy for superficial bladder cancer. The procedure involves repeated instillations of BCG following endoscopic resection. A T-cell-centric delayed host response occurs in the damaged bladder mucosa, ultimately conferring a tumor immunotherapeutic potential in the process [2].

While usually well tolerated, BCG instillation is, ultimately, an iatrogenic UTI, running the risk of, however low, both local and systemic complications with some cases reaching fatal results. Hence, the proper understanding of the various forms of presentation of BCG induced adverse events and their management is necessary when treating superficial bladder cancer patients with intravesical BCG instillation.

2 Methods

A systemic literature search was performed for the last 30 years in MEDLINE with the terms “Bacillus Calmette-Guerin”, “BCG”, “superficial bladder cancer”, “intravesical instillation”, and “complications” to identify literature pertaining to the subject since its introduction. Only peer reviewed articles written in the English language were included.

The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using ICUD standards [3], [4].

3 Scope of clinical response and complications

3.1 Self-limiting response

The difficulty in properly collating evidence defining BCG related complications primarily lies in its nature as a form of UTI. Patients commonly experience self-limiting symptoms along the spectrum of irritative voiding to flu-like symptoms following instillation [5], [6]. Patients commonly complain of urgency, dysuria, frequency, and even hematuria, as well as low grade fever and malaise, limited, mostly within 24 to 48 hours following instillation. However, this is expected, as the therapeutic action of BCG itself involves release of a wide spectrum of inflammatory cytokines and local recruitment and infiltration of neutrophils, monocytes, and T-lymphocytes [7]. In fact, elevated levels of IL-2 have been suggested to correlate with a positive outcome, whereas low levels suggested a greater likelihood of tumor recurrence [8], [9], [10]. Hence, these symptoms are generally regarded as a sign of adequate treatment effect [11]. These presentations are similar to those following BCG vaccination and are expected to pass without further treatment [12], [13].

3.2 Systemic complications

The incidence of systemic BCG infection has been reported to present from 3 to 7% [13], [14], [15], [16]. The scope of these complications range from fever, malaise, chills, sweats, weight loss, shortness of breath, and arthralgia, and accounts for one third of cases involving BCG infection [13], [14], [15], [16]. However, less commonly complications such as hepatitis [17], [18], [19], [20], [21], [22], [23], polyarthritis [24], [25], [26], or prosthetic joint infection [27] have also been reported, suggesting high level of clinical suspicion is required addressing atypical infective symptoms following BCG instillation.

Most systemic presentations generally appear earlier, within 8 to 12 weeks following instillation and up to 1 year [13]. Several risk factors for developing BCG systemic infection have been suggested, such as, recent interval to procedures breaching urothelial mucosal integrity, and poor technique during administration [28], [29], [30]. However, the paucity of studies constituted only anecdotal evidence, further aggravated by the possibility a missed diagnosis where confirmation by culture or PCR assay might have provided false negative results. Two studies have failed to show correlation between time from recent TUR to BCG instillation [6], [16].

The importance of a high level of suspicion in diagnosing these patients is again stressed, as previous literature show that culture of biopsied tissue was less likely to yield positive results (31%) compared to later forms of more localized presentations (64%) [13]. However, many cases might have missed diagnosis due to lack of utilizing newer PCR-based assays [16], [30], [31].

The most dangerous complication is systemic sepsis, characterized by chills, fever, hypotension, and progressive multiorgan failure. The incidence is reported to be 0.3–0.4% [6], [13], [32].

3.3 Localized complications

In contrast to systemic complications, localized complications generally occur later (>1 year in most literature), without generalized symptoms such as fever and chills. Biopsy of the affected tissue reveals non-caseating granulomas, and there is higher probability of positive cultures for mycobacteria than earlier systemic diseases [33], [34], [35], [36], [37], [38], [39], [40]. While most localized complications occurred in areas in contact with the urinary tract (penis, prostate, bladder, kidney), distant localizations in the vasculature [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], vertebrae [28], [29], [30], [49], chest wall [52], and other granulomatous abscess in rarer localizations have been reported [53], [54], [55], [56].

Granulomas are uniformly present, and the disease appears to have been spread by either contiguous or hematogenous means.

Genitourinary complications presented as abscesses or ulcerations in tissue in direct contiguous contact. Bladder [35], penile [57], prostate [58], and renal [40], [59], [60], [61] generally present as a localized abscess with a benign course of disease. However, rare complications involving the vasculature, resulting in aneurysms have shown poorer prognosis with mortality rate of 15.8% [41], [42], [62].

4 Diagnosis

Microbiologic and histologic diagnosis can be performed, however, some cases are reported solely based on clinical manifestations. Diagnosis by acid-fast bacilli staining was 25.3%, 40.9% for mycobacterial culture, and 41.8% for PCR-based assays [16]. Granulomatous inflammation was present in 86.3% of biopsied cases.

5 Treatment

With an overall lack of clinical trials, as well as due to the paucity of cases reported, there is no clear guideline. However, most reports suggest the use of antituberculosis medications with or without corticosteroids or surgery. Standard recommended therapy for M. tuberculosis of INH and RIF for 6 months with a 2 month intensive phase including EMB is generally recommended [63], [64]. Alternatively, Gonzalez et al. recommended the treatment regimen of 9 months, as BCG is intrinsically resistant to PZA, requiring a longer treatment period [13]. Some strains (Connaught, Tice, RIVM) have shown to be resistant to cycloserine [65]. Connaught BCG strain is susceptible to fluoroquinolones, and reports have shown successful treatment replacing RIF and INH [13], [57], [65], [66], [67]. Corticosteroids were mostly used in the presence of miliary tuberculosis [18], [64].

No trial has tested whether or not terminating, delaying or continuing BCG instillation was appropriate. However, the consensus suggests discontinuation of BCG instillation in case of previous systemic BCG infection [13], [64], [68].

6 Outcomes

The overall prognosis is good, however, Asín et al. presented an overall mortality of 5.4%. No studies reported risk factors for poorer outcomes, while Asín et al. found age older than 65, disseminated infection, and vascular involvement to be significantly related to higher mortality in a composite study of collected patients from a single institute and comparable case review of the literature [16].


References

[1] Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-guerin in the Treatment of Superficial Bladder Tumors. J Urol. 1976 Aug;116(2):180–2. DOI: 10.1016/S0022-5347(17)58737-6
[2] Ingersoll MA, Albert ML. From infection to immunotherapy: host immune responses to bacteria at the bladder mucosa. Mucosal Immunol. 2013 Nov;6(6):1041-53. DOI: 10.1038/mi.2013.72
[3] Abrams P, Khoury S, Grant A. Evidence--based medicine overview of the main steps for developing and grading guideline recommendations. Prog Urol. 2007 May;17(3):681-4. DOI: 10.1016/S1166-7087(07)92383-0
[4] Public Health Service, Agency for Health Care Policy and Research. Acute Pain Management: Operative Or Medical Procedures and Trauma. Clinical Practice Guideline. Rockville: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1992.
[5] Koya MP, Simon MA, Soloway MS. Complications of intravesical therapy for urothelial cancer of the bladder. J Urol. 2006 Jun;175(6):2004-10. DOI: 10.1016/S0022-5347(06)00264-3
[6] Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, Gontero P, Turkeri L, Marreaud S, Collette S, Oosterlinck W. Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol. 2014 Jan;65(1):69-76. DOI: 10.1016/j.eururo.2013.07.021
[7] Alexandroff AB, Nicholson S, Patel PM, Jackson AM. Recent advances in bacillus Calmette-Guerin immunotherapy in bladder cancer. Immunotherapy. 2010 Jul;2(4):551-60. DOI: 10.2217/imt.10.32
[8] Watanabe E, Matsuyama H, Matsuda K, Ohmi C, Tei Y, Yoshihiro S, Ohmoto Y, Naito K. Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guérin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol Immunother. 2003 Aug;52(8):481-6. DOI: 10.1007/s00262-003-0384-9
[9] Zuiverloon TC, Nieuweboer AJ, Vékony H, Kirkels WJ, Bangma CH, Zwarthoff EC. Markers predicting response to bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: a systematic review. Eur Urol. 2012 Jan;61(1):128-45. DOI: 10.1016/j.eururo.2011.09.026
[10] Saint F, Kurth N, Maille P, Vordos D, Hoznek A, Soyeux P, Patard JJ, Abbou CC, Chopin DK. Urinary IL-2 assay for monitoring intravesical bacillus Calmette-Guérin response of superficial bladder cancer during induction course and maintenance therapy. Int J Cancer. 2003 Nov;107(3):434-40. DOI: 10.1002/ijc.11352
[11] Böhle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J Urol. 2003 Sep;170(3):964-9. DOI: 10.1097/01.ju.0000073852.24341.4a
[12] Casanova JL, Blanche S, Emile JF, Jouanguy E, Lamhamedi S, Altare F, Stéphan JL, Bernaudin F, Bordigoni P, Turck D, Lachaux A, Albertini M, Bourrillon A, Dommergues JP, Pocidalo MA, Le Deist F, Gaillard JL, Griscelli C, Fischer A. Idiopathic disseminated bacillus Calmette-Guérin infection: a French national retrospective study. Pediatrics. 1996 Oct;98(4 Pt 1):774-8.
[13] Gonzalez OY, Musher DM, Brar I, Furgeson S, Boktour MR, Septimus EJ, Hamill RJ, Graviss EA. Spectrum of bacille Calmette-Guérin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis. 2003 Jan;36(2):140-8. DOI: 10.1086/344908
[14] Resel Folkersma L, Olivier Gómez C, San José Manso L, Veganzones de Castro S, Galante Romo I, Vidaurreta Lázaro M, de la Orden GV, Arroyo Fernández M, Díaz Rubio E, Silmi Moyano A, Maestro de Las Casas MA. Immunomagnetic quantification of circulating tumoral cells in patients with prostate cancer: clinical and pathological correlation. Arch Esp Urol. 2010 Jan-Feb;63(1):23-31. DOI: 10.4321/S0004-06142010000100004
[15] Steg A, Sicard D, Leleu C, Debré B, Boccon-Gibod L. Systemic complications of intravesical BCG therapy for bladder cancer. Lancet. 1985 Oct 19;2(8460):899. 10.1016/S0140-6736(85)90169-2
[16] Pérez-Jacoiste Asín MA, Fernández-Ruiz M, López-Medrano F, Lumbreras C, Tejido A, San Juan R, Arrebola-Pajares A, Lizasoain M, Prieto S, Aguado JM. Bacillus Calmette-Guérin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: incidence, risk factors, and outcome in a single-institution series and review of the literature. Medicine (Baltimore). 2014 Oct;93(17):236-54. DOI: 10.1097/MD.0000000000000119
[17] Gao CQ, Mithani R, Leya J, Dawravoo L, Bhatia A, Antoine J, De Alba F, Russo PA, Fimmel CJ. Granulomatous hepatitis, choroiditis and aortoduodenal fistula complicating intravesical Bacillus Calmette-Guérin therapy: Case report. BMC Infect Dis. 2011 Sep;11:260. DOI: 10.1186/1471-2334-11-260
[18] Adami M, Marsteller I, Mazzucchelli L, Cerny A, Bernasconi E, Bertoli R. Granulomatous hepatitis after intravesical bacillus Calmette-Guérin treatment. Scand J Infect Dis. 2011 Jan;43(1):55-7. DOI: 10.3109/00365548.2010.515609
[19] Soylu A, Ince AT, Polat H, Yasar N, Ciltas A, Ozkara S, Tasci AI. Peritoneal tuberculosis and granulomatous hepatitis secondary to treatment of bladder cancer with Bacillus Calmette-Guérin. Ann Clin Microbiol Antimicrob. 2009 Apr;8:12. DOI: 10.1186/1476-0711-8-12
[20] Van Outryve SM, Francque SM, Gentens PA, De Pauw FF, Van den Bogaert E, Van Marck EA, Pelckmans PA, Michielsen PP. Bacillus Calmette-Guérin-induced granulomatous hepatitis in a patient with a superficial bladder carcinoma. Eur J Gastroenterol Hepatol. 2004 Oct;16(10):1027-32. DOI: 10.1097/00042737-200410000-00012
[21] Trevenzoli M, Cattelan AM, Marino F, Sasset L, Donà S, Meneghetti F. Sepsis and granulomatous hepatitis after bacillus Calmette-Guerin intravesical installation. J Infect. 2004 May;48(4):363-4. DOI: 10.1016/j.jinf.2004.01.013
[22] Leebeek FW, Ouwendijk RJ, Kolk AH, Dees A, Meek JC, Nienhuis JE, Dingemans-Dumas AM. Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation. Gut. 1996 Apr;38(4):616-8. DOI: 10.1136/gut.38.4.616
[23] Thompson D, Cumming J. Granulomatous hepatitis following intravesical BCG therapy. Br J Urol. 1990 Oct;66(4):432-3. DOI: 10.1111/j.1464-410X.1990.tb14971.x
[24] Pardalidis NP, Papatsoris AG, Kosmaoglou EV, Georganas C. Two cases of acute polyarthritis secondary to intravesical BCG adjuvant therapy for superficial bladder cancer. Clin Rheumatol. 2002 Nov;21(6):536-7. DOI: 10.1007/s100670200131
[25] Onur O, Celiker R. Polyarthritis as a complication of intravesical bacillus Calmette-Guerin immunotherapy for bladder cancer. Clin Rheumatol. 1999;18(1):74-6. DOI: 10.1007/s100670050059
[26] Hammadeh MY, Dutta SN, Worrall JG, Morgan RJ. Acute reactive polyarthritis after intravesical bacillus Calmette-Guèrin instillation. Br J Urol. 1995 Dec;76(6):811-2. DOI: 10.1111/j.1464-410X.1995.tb00788.x
[27] Gomez E, Chiang T, Louie T, Ponnapalli M, Eng R, Huang DB. Prosthetic Joint Infection due to Mycobacterium bovis after Intravesical Instillation of Bacillus Calmette-Guerin (BCG). Int J Microbiol. 2009;2009:527208. DOI: 10.1155/2009/527208
[28] Civen R, Berlin G, Panosian C. Vertebral osteomyelitis after intravesical administration of bacille Calmette-Guérin. Clin Infect Dis. 1994 Jun;18(6):1013-4. DOI: 10.1093/clinids/18.6.1013
[29] Katz DS, Wogalter H, D'Esposito RF, Cunha BA. Mycobacterium bovis vertebral osteomyelitis and psoas abscess after intravesical BCG therapy for bladder carcinoma. Urology. 1992 Jul;40(1):63-6. DOI: 10.1016/0090-4295(92)90439-4
[30] Nikaido T, Ishibashi K, Otani K, Yabuki S, Konno S, Mori S, Ohashi K, Ishida T, Nakano M, Yamaguchi O, Suzutani T, Kikuchi S. Mycobacterium bovis BCG vertebral osteomyelitis after intravesical BCG therapy, diagnosed by PCR-based genomic deletion analysis. J Clin Microbiol. 2007 Dec;45(12):4085-7. DOI: 10.1128/JCM.01714-07
[31] Heemstra KA, Bossink AW, Spermon R, Bouwman JJ, van der Kieft R, Thijsen SF. Added value of use of a purified protein derivative-based enzyme-linked immunosorbent spot assay for patients with Mycobacterium bovis BCG infection after intravesical BCG instillations. Clin Vaccine Immunol. 2012 Jun;19(6):974-7. DOI: 10.1128/CVI.05597-11
[32] Garyfallou GT. Mycobacterial sepsis following intravesical instillation of bacillus Calmette-Guérin. Acad Emerg Med. 1996 Feb;3(2):157-60. DOI: 10.1111/j.1553-2712.1996.tb03405.x
[33] Kureshi F, Kalaaji AN, Halvorson L, Pittelkow MR, Davis MD. Cutaneous complications of intravesical treatments for bladder cancer: granulomatous inflammation of the penis following BCG therapy and penile gangrene following mitomycin therapy. J Am Acad Dermatol. 2006 Aug;55(2):328-31. DOI: 10.1016/j.jaad.2005.07.041
[34] Del Prete R, Ditonno P, Mosca A, Battaglia M, PaoloSelvaggi F, Miragliotta G. BCG septicemia after radical cystectomy: a rare postoperative complication following BCG therapy. J Infect. 2002 Aug;45(2):112-4. DOI: 10.1053/jinf.2002.1025
[35] Ströck V, Dotevall L, Sandberg T, Gustafsson CK, Holmäng S. Late bacille Calmette-Guérin infection with a large focal urinary bladder ulceration as a complication of bladder cancer treatment. BJU Int. 2011 May;107(10):1592-7. DOI: 10.1111/j.1464-410X.2010.09923.x
[36] Harving SS, Asmussen L, Roosen JU, Hermann G. Granulomatous epididymo-orchitis, a rare complication of intravesical bacillus Calmette-Guérin therapy for urothelial cancer. Scand J Urol Nephrol. 2009;43(4):331-3. DOI: 10.1080/00365590902930808
[37] Aust TR, Massey JA. Tubercular prostatic abscess as a complication of intravesical bacillus Calmette-Guérin immunotherapy. Int J Urol. 2005 Oct;12(10):920-1. DOI: 10.1111/j.1442-2042.2005.01183.x
[38] Hansen CP, Mortensen S. Epididymo-orchitis and Reiter's disease. Two infrequent complications after intravesical bacillus Calmette-Guérin therapy. Scand J Urol Nephrol. 1997 Jun;31(3):317-8. DOI: 10.3109/00365599709070359
[39] Erol A, Ozgür S, Tahtali N, Akbay E, Dalva I, Cetin S. Bacillus Calmette-Guerin (BCG) balanitis as a complication of intravesical BCG immunotherapy: a case report. Int Urol Nephrol. 1995;27(3):307-10. DOI: 10.1007/BF02564767
[40] Modesto A, Marty L, Suc JM, Kleinknecht D, de Frémont JF, Marsepoil T, Veyssier P. Renal complications of intravesical bacillus Calmette-Guérin therapy. Am J Nephrol. 1991;11(6):501-4. DOI: 10.1159/000168368
[41] Roylance A, Mosley J, Jameel M, Sylvan A, Walker V. Aorto-enteric fistula development secondary to mycotic abdominal aortic aneurysm following intravesical bacillus Calmette-Guerin (BCG) treatment for transitional cell carcinoma of the bladder. Int J Surg Case Rep. 2013;4(1):88-90. DOI: 10.1016/j.ijscr.2012.09.009
[42] Maundrell J, Fletcher S, Roberts P, Stein A, Lambie M. Mycotic aneurysm of the aorta as a complication of Bacillus Calmette-Guérin instillation. J R Coll Physicians Edinb. 2011 Jun;41(2):114-6. DOI: 10.4997/JRCPE.2011.203
[43] Costiniuk CT, Sharapov AA, Rose GW, Veinot JP, Desjardins M, Brandys TM, Suh KN. Mycobacterium bovis abdominal aortic and femoral artery aneurysms following intravesical bacillus Calmette-Guérin therapy for bladder cancer. Cardiovasc Pathol. 2010 Mar-Apr;19(2):e29-32. DOI: 10.1016/j.carpath.2008.09.003
[44] Coscas R, Arlet JB, Belhomme D, Fabiani JN, Pouchot J. Multiple mycotic aneurysms due to Mycobacterium bovis after intravesical bacillus Calmette-Guérin therapy. J Vasc Surg. 2009 Nov;50(5):1185-90. DOI: 10.1016/j.jvs.2009.06.004
[45] Harding GE, Lawlor DK. Ruptured mycotic abdominal aortic aneurysm secondary to Mycobacterium bovis after intravesical treatment with bacillus Calmette-Guérin. J Vasc Surg. 2007 Jul;46(1):131-4. DOI: 10.1016/j.jvs.2007.01.054
[46] Witjes JA, Vriesema JL, Brinkman K, Bootsma G, Barentsz JO. Mycotic aneurysm of the popliteal artery as a complication of intravesical BCG therapy for superficial bladder cancer. Case report and literature review. Urol Int. 2003;71(4):430-2. DOI: 10.1159/000074100
[47] Farber A, Grigoryants V, Palac DM, Chapman T, Cronenwett JL, Powell RJ. Primary aortoduodenal fistula in a patient with a history of intravesical therapy for bladder cancer with bacillus Calmette-Guérin: review of primary aortoduodenal fistula without abdominal aortic aneurysm. J Vasc Surg. 2001 Apr;33(4):868-73. DOI: 10.1067/mva.2001.112327
[48] Damm O, Briheim G, Hagström T, Jönsson B, Skau T. Ruptured mycotic aneurysm of the abdominal aorta: a serious complication of intravesical instillation bacillus Calmette-Guerin therapy. J Urol. 1998 Mar;159(3):984. DOI: 10.1016/S0022-5347(01)63796-0
[49] Rozenblit A, Wasserman E, Marin ML, Veith FJ, Cynamon J, Rozenblit G. Infected aortic aneurysm and vertebral osteomyelitis after intravesical bacillus Calmette-Guérin therapy. AJR Am J Roentgenol. 1996 Sep;167(3):711-3. DOI: 10.2214/ajr.167.3.8751686
[50] Wolf YG, Wolf DG, Higginbottom PA, Dilley RB. Infection of a ruptured aortic aneurysm and an aortic graft with bacille Calmette-Guérin after intravesical administration for bladder cancer. J Vasc Surg. 1995 Jul;22(1):80-4. DOI: 10.1016/S0741-5214(95)70092-7
[51] Bornet P, Pujade B, Lacaine F, Bazelly B, Paquet JC, Roland J, Huguier M. Tuberculous aneurysm of the femoral artery: a complication of bacille Calmette-Guérin vaccine immunotherapy--a case report. J Vasc Surg. 1989 Dec;10(6):688-92. DOI: 10.1016/0741-5214(89)90014-1
[52] Kanamori H, Isogami K, Hatakeyama T, Saito H, Shimada K, Uchiyama B, Aso N, Kaku M. Chest wall abscess due to Mycobacterium bovis BCG after intravesical BCG therapy. J Clin Microbiol. 2012 Feb;50(2):533-5. DOI: 10.1128/JCM.05888-11
[53] Leis JA, Ricciuto DR, Gold WL. Attenuated but live: a pelvic abscess caused by bacille Calmette-Guerin. CMAJ. 2011 Sep;183(13):1511-4. DOI: 10.1503/cmaj.101853
[54] Talluri SK, Marigowda L, Besur S, Talluri J, Forstall GJ. A report of iliac muscle abscess due to Mycobacterium bovis after bacillus Calmette-Guerin therapy for bladder cancer. South Med J. 2010 Apr;103(4):369-70. DOI: 10.1097/SMJ.0b013e3181d38ff1
[55] Alvarez-Múgica M, Gómez JM, Vázquez VB, Monzón AJ, Rodríguez JM, Robles LR. Pancreatic and psoas abscesses as a late complication of intravesical administration of bacillus Calmette-Guerin for bladder cancer: a case report and review of the literature. J Med Case Rep. 2009 Sep;3:7323. DOI: 10.4076/1752-1947-3-7323
[56] Martinez-Caceres P, Rubio-Briones J, Palou J, Salvador J, Vicente J. Prevesical and inguinal abscess following intravesical BCG instillation. Scand J Urol Nephrol. 1998 Dec;32(6):409-10. DOI: 10.1080/003655998750015205
[57] García Baldoví M, Pérez-Crespo M, Onrubia J, Moragón M. Granulomatous balanitis after intravesical Bacille Calmette-Guérin instillation. Actas Dermosifiliogr. 2013 Apr;104(3):251-2. DOI: 10.1016/j.ad.2012.06.008
[58] Matlaga BR, Veys JA, Thacker CC, Assimos DG. Prostate abscess following intravesical bacillus Calmette-Guerin treatment. J Urol. 2002 Jan;167(1):251. DOI: 10.1016/S0022-5347(05)65430-4
[59] Senés AT, Badet L, Lyonnet D, Rouvière O. Granulomatous renal masses following intravesical bacillus Calmette Guérin therapy: the central unaffected calyx sign. Br J Radiol. 2007 Oct;80(958):e230-3. DOI: 10.1259/bjr/42250860
[60] Wada Y, Sugiyama Y, Kikukawa H, Kuwahara T, Takahashi W, Takamiya T, Ueda S. Isolated renal tuberculosis following intravesical Bacillus Calmette-Guérin therapy for bladder cancer. Urol Int. 2004;72(3):257-60. DOI: 10.1159/000077126
[61] Rocha Mde S, Campagnari JC. Granulomatous renal mass after treatment with intravesical bacille Calmette-Guérin. AJR Am J Roentgenol. 1994 Oct;163(4):996-7. DOI: 10.2214/ajr.163.4.8092061
[62] Somoskovi A, Carlyn C, Dormandy J, Salfinger M. Mediastinal mass mimicking a tumor in a patient with bladder cancer after Bacillus Calmette-Guerin treatment. Eur J Clin Microbiol Infect Dis. 2007 Dec;26(12):937-40. DOI: 10.1007/s10096-007-0390-5
[63] Bacille Calmette-Guèrin (BCG) Vaccination. In: Kirch W, Editor. Encyclopedia of Public Health. New York: Springer Science+Business Media; 2008. p. 57.
[64] Rischmann P, Desgrandchamps F, Malavaud B, Chopin DK. BCG intravesical instillations: recommendations for side-effects management. Eur Urol. 2000;37 Suppl 1:33-6. DOI: 10.1159/000052381
[65] Durek C, Rüsch-Gerdes S, Jocham D, Böhle A. Sensitivity of BCG to modern antibiotics. Eur Urol. 2000;37 Suppl 1:21-5. DOI: 10.1159/000052378
[66] Griggs H, Cammarata SK. Acute mental changes in a 68-year-old man with bladder cancer. Chest. 1998 Aug;114(2):621-3. DOI: 10.1378/chest.114.2.621
[67] Manfredi R, Dentale N. Pulmonary and disseminated tubercular disease by Bacillus of Calmette-Guérin after administration as a local adjuvant immunotherapy of relapsing bladder adenocarcinoma. Retrovirology. 2010;7(Suppl 1):P91. DOI: 10.1186/1742-4690-7-S1-P91
[68] Lamm DL. Efficacy and safety of bacille Calmette-Guérin immunotherapy in superficial bladder cancer. Clin Infect Dis. 2000 Sep;31 Suppl 3:S86-90. DOI: 10.1086/314064