Infectious Diseases, 2015; Early Online: 1–7
Original Article
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Complications following intravesical bacillus Calmette-Guerin treatment for bladder cancer: a case series of 22 patients J.D. Pommier1, N. Ben Lasfar1, N. Van Grunderbeeck2, C. Burdet3,4, C. LaouÉnan3,4,5, C. Rioux1, C. Pierre-Audigier6, A. Meybeck7, L. Choudat8, A. Benchikh5,9, S. Nguyen10, E. Bouvet1,5, P. Yeni1,4,5, Y. Yazdanpanah1,4,5 & V. Joly1,4 1Infectious
and Tropical Diseases Department, Bichat Hospital, AP-HP, Paris, 2Intermediate and Intensive Care Units, Hospital Center, Lens, 3Biostatistics Department, Bichat Hospital, AP-HP, Paris, 4IAME, UMR 1137, INSERM, Paris, 5Paris Diderot University, Sorbonne Paris Cité, Paris, 6Microbiology Department, Bichat Hospital, AP-HP, Paris, 7Intensive Care Unit, Hospital Center, Tourcoing, 8Pathology Department, Bichat Hospital, AP-HP, Paris, 9Urology Department, Bichat Hospital, AP-HP, Paris, and 10Infectious Disease Department, Hospital Center, Tourcoing, France
Abstract Background: Intravesical bacillus Calmette-Guerin (BCG) therapy is an effective and widely used treatment for superficial bladder carcinoma. Local complications are frequent whereas systemic complications are rare but can be serious, and their management is not well known. Methods: We describe retrospectively the records of 22 patients treated in 3 infectious disease departments, for complications related to intravesical BCG therapy as treatment of bladder cancer. Results: All the patients were male, with a median age of 68 years (range 56–88). Complications occurred after a median of 5 instillations (range 1–11) and were observed within 24 h following BCG instillation for 14 patients. Common symptoms were fever (n 20), impaired general condition (n 14), and shortness of breath (n 7). Six patients had a systemic septic reaction leading to transfer into the intensive care unit for five of them. Lung infiltration was the most frequent presentation (n 11). Mycobacterium bovis was isolated from only two patients, but histology showed the presence of a granuloma in nine patients. Antimycobacterial treatment was initialized in 17 patients; the outcome was favorable in 16 patients, with a median length of symptoms resolution of 22.5 days (range 5–425 days). Eleven patients received corticosteroids in addition to specific treatment and had a more rapid improvement. One patient died with disseminated BCGitis proved by biopsy. Conclusions: Complications following intravesical BCG therapy are rare but can be severe and fatal. Histology seems to be the method that contributes most in confirmation of the diagnosis. Antimycobacterial therapy is effective, and probably more efficient when combined with corticosteroids, but the regimen and duration of the treatment are not standardized.
Keywords: BCG; bladder cancer; intravesical instillation; Mycobacterium bovis
Introduction Bacillus Calmette-Guerin (BCG) is commonly used as a vaccine to prevent tuberculosis. It is also used as an intravesical immunotherapy to treat superficial bladder cancer [1,2]. Several reports have described its efficacy as an alternative to chemotherapy [3–5], making it currently the gold standard in the treatment of urothelial carcinoma of the bladder with intermediate or high risk of progression and recurrence, in case of no muscle involvement [2,6,7].
However, the optimal number and frequency of repeated injections of BCG are not well defined [8]. BCG is a live attenuated strain of Mycobacterium bovis supposed to interact locally with the immune system after intravesical injection, leading to cellmediated immunity targeting bladder cancer [9,10]. Complications that occur after intravesical BCG therapy are mostly local reactions such as cystitis and hematuria [11–13]. A review of 2602 patients receiving intravesical BCG therapy reported major adverse
Correspondence: Jean-David Pommier, Services des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, 46 Rue Henri Huchard, 75018 Paris, France. Tel: 33 6 88438181. E-mail: [email protected] (Received 6 February 2015; accepted 25 May 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1055794
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events in less than 5% of patients [12]. More recently systemic side effects were reported to occur in 30% of 1316 patients, including fever in 10% [14]. The main complications are granulomatous prostatitis, pneumonitis, and hepatitis, as well as systemic septic reactions. Systemic septic reaction can sometimes lead to death [15]. The diagnosis of adverse events may be difficult due to the lack of precise diagnosis criteria and the infrequent isolation of M. bovis. Many clinical cases have been reported [16–19] but few series are available [20,21]. To our knowledge, the most important series was reported in 2003 [20], describing the clinical presentation in eight patients. More accurate diagnostic criteria for complications of intravesical BCG therapy (BCGitis) would allow clinicians to optimize their management and would in particular be helpful to define the situations in which BCG therapy has to be interrupted. The aim of this retrospective study was: (i) to describe the clinical and biological characteristics of patients with major complications following intravesical BCG therapy for urothelial cancer; (ii) to describe the management of these patients; and (iii) to describe the evolution of complications following intravesical BCG therapy.
Materials and Methods We retrospectively studied records of patients who had been referred to an infectious disease department for BCGitis after intravesical instillation of BCG, performed for the treatment of biopsy-proved bladder cancer. Patients came from three large centers, the Infectious Disease Department of the university hospitals of Lille and Tourcoing (from January 1999 to December 2006) and the Infectious and Tropical Disease Department of BichatClaude Bernard Hospital, a university hospital in Paris (from January 2007 to December 2011). Complications were assessed during the year following intravesical BCG therapy. BCGitis was defined as: the occurrence of fever ( 38°C) without any other etiology, lasting more than 48 h, and/or at least one organ involvement other than the bladder, that led to discontinuation of BCG therapy. The diagnosis of organ involvement was based on clinical, biological, and radiological abnormalities. Among organ involvements, lung injury was defined as a radiological lung infiltrates and liver involvement was defined as an increase in alkaline phosphatase and gamma glutamine transferase (GGT) or in alanine and/or aspartate aminotransferases (ALT or AST) 1.5 times the upper limit of normal (ULN).
Cases were included whether or not there was a microbiological identification of M. bovis by culture, polymerase chain reaction (PCR) or histological confirmation (granulomas, with or without caseous necrosis). We distinguished local reactions limited to the genito-urinary tract and systemic reactions involving at least one site other than the genito-urinary tract. Severe systemic reactions were defined by the occurrence of septic shock syndrome. Results were expressed as absolute number and percentage for categorical variables, and median and range for continuous quantitative variables.
Results We report 22 cases of BCGitis after intravesical BCG therapy, 11 from the Lille and Tourcoing hospitals and 11 from Bichat Claude Bernard hospital.
Clinical characteristics The patients were all male, with a median age of 68 years (range 56–88 years). There was a history of Crohn’s disease, tuberculosis, and diabetes for one, two, and four patients, respectively. Other comorbidities included hypertension (n 7), coronary artery disease (n 3), and chronic obstructive pulmonary disease (COPD) (n 1). No patient was receiving steroids or immunosuppressive therapy at the time of BCG therapy. According to TNM grading (WHO 1973) and staging of urothelial carcinoma, tumors were classified as G1pTa (n 2), G2pTa (n 3), G3pTa (n 5), G2pT1 (n 1), or G3pT1 (n 6). Pathological findings were unknown in six cases. All complications occurred between the first and the eleventh instillations, after a median of 5 instillations. Severe reactions occurred earlier in the BCG therapy cycle (median of 3 instillations instead of 6). In 14 cases, complications were observed in the first 24 h after instillation; in the remaining cases, the median delay of occurrence was 13.5 days (range 3–19 days). The most common symptoms were fever 38°C (n 20, 91%), impaired general condition (n 14, 64%), and shortness of breath (n 7, 31%). The other symptoms are detailed in Table I. Two patients had only local complications, 1 had isolated fever, 16 had disseminated reactions, and 3 had local and disseminated complications. Organ involvement was almost constant (n 21) and often multiple (n 15, 77%). Six patients (27%) had a systemic septic reaction with hypotension, including five patients with multiorgan failure needing transfer into an intensive
Complications following intravesical BCG Biological characteristics
Table I. Clinical characteristics of the 22 patients. No. of patients (%)
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Characteristics Symptoms Fever Impaired general condition Shortness of breath Hypotension Urinary disorders Sweats Arthralgia Cough Conjunctivitis Organ involvement Disseminated Lung infiltration With hypoxemia Hepatitis Renal failure (creatininemia 120 mmol/L) Heart involvement Arthritis Vertebral osteomyelitis Pancreatic abscess Psoas abscess Locoregional Orchiepididymitis Granulomatous prostatitis Glans involvement Distribution of patients according to organ involvement Lung infiltration only Lung infiltration and other organ involvement Organ involvement without lung involvement Isolated fever
20 14 7 6 5 4 3 3 2
(91) (64) (32) (27) (23) (18) (14) (14) (9)
Abnormal white blood cell counts occurred in seven patients ( 12 000/ml among two patients and 4000/ml among five patients) and abnormal platelet counts ( 150 000/ml) in five patients (including 50 000 /ml in two patients). C-reactive protein (CRP) level was available for 16 patients and was always increased, with a median of 83 mg/L (range 12–296). Renal insufficiency with creatininemia 120 mmol/L occurred in nine patients (41%). Microbiological and histological characteristics
11 4 13 9 2 2 1 1 1
(50) (36) (59) (41) (9) (9) (5) (5) (5)
3 (14) 1 (5) 1 (5)
1 10 10 1
(5) (46) (46) (5)
care unit. Among these six patients, symptoms occurred in the 24 h following the instillation after a median of 3 instillations (range 2–11).
Twenty-eight microbiological samples were obtained from 17 patients (77%). Three patients had a positive acid-fast bacilli (AFB) smear, including two subjects with a positive culture for M. bovis. PCR was positive in only one of the five patients tested. This positive PCR was obtained from a bone marrow sample, while culture and direct examination were negative for mycobacteria. Biopsy was contributive in 9 of 10 patients, showing epithelioïd granuloma without caseous necrosis in 7 patients and with necrosis in 2 patients. Only one patient had both a positive culture for M. bovis and a granuloma on a vertebral sample. Details of microbiological and histology characteristics are summarized in Table II. Treatment and evolution Antibiotics were introduced in 12 patients (55%) while the diagnosis of BCGitis was pending.
Table II. Results of bacteriological and histological analysis. Bacteriology Sputum Bronchoalveolar lavage Tracheal aspiration Urine Joint liquid CSF Bone marrow Others Histology Lung Bronchial Transbronchial Post mortem Liver Prostate Testicles Vertebra Kidney Glans
3
No. of samples studied
AFB-positive (no. of samples)
Culture positive for M.bovis (no. of samples)
7 2 3 6 3 2 2 3
0 0 0 1 1 0 1 0
0 0 0 0 1 0 1 0
No. of samples studied
Non-caseous granuloma (no. of samples)
Caseous granuloma (no. of samples)
6 4 1 1 3 1 1 1 1 1
3 1 1 1 3 1 0 1 0 0
0 0 0 0 0 0 1 0 0 1
AFB, acid-fast bacilli; CSF, cerebrospinal fluid.
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Third-generation cephalosporins (3GC) (n 8, 67%) and fluoroquinolones (n 7, 58%) were the most frequently used antibiotics. Antituberculous drugs were initiated in 17 patients (77%). The majority of them (n 16) had a disseminated BCGitis; the remaining patient had a testicular nodule, in which histological examination revealed a granuloma that did not resolve spontaneously. Most of the patients with a microbiologically or histologically confirmed diagnosis were treated (n 10, 91%). The types of drugs used are described in Table III. The delay before initiation of antituberculosis drugs was variable, with a median of 12 days (range 1–90 days) after the onset of symptoms, two patients being treated as soon as the first day of symptoms. Treatment was prescribed with a median length of 6 months (range 0.75–16 months) for rifampicin and isoniazid and of 2 months (range 2–3 months) for ethambutol. Corticosteroids were associated with the initial phase of antituberculosis treatment in 65% of cases (n 11), including all patients with a severe systemic reaction. The median duration of corticotherapy was 8 weeks (range 1–16 weeks). The outcome was favorable in 95% of cases (n 21). Fever resolved after a median of 6 days (range 0–7 days) of therapy. The median length of hospital duration and symptoms resolution after the introduction of antituberculosis treatment was 15.0 (range 1–60) days and 22.5 days (range 5–425), respectively. Symptoms resolved more rapidly when corticosteroids were added, i.e. 15 days (range 5–44) instead of 105 days (range 11–425). One patient died after a systemic severe reaction with multiorgan failure while the treatment was started the first day Table III. Therapeutic regimens. Regimen Antituberculous drugs H HR HRE HREZ Corticosteroid therapy Combined with antituberculous drugs Isolated Antibiotics other than antituberculous drugs Without antituberculous drugs Fluoroquinolones Othersa Before treatment with antituberculous drugs Fluoroquinolones Othersa
No. of patients (%) 2 2 10 3
(9) (9) (45) (14)
11 0 12 5 2 3 7 5 2
(65) (0) (55) (23) (9) (14) (32) (23) (9)
E, ethambutol; H, isoniazid; R, rifampicin; Z, pyrazinamide. Antituberculosis drugs were given at usual dosages: H, 3–5 mg/kg; R, 10 mg/kg; E, 20 mg/kg. aAntibiotics without activity against M.bovis.
with antituberculosis drugs and corticosteroids. Postmortem histology revealed pulmonary and hepatic granulomas without necrosis. Five patients did not receive antituberculosis drugs, antibiotics or corticosteroids. All of them had fever, three had disseminated reaction: one had lung infiltration and two had hepatitis; one had only locoregional reaction and one had isolated fever. The median time of onset of symptoms was 1 day (range 1–42 days). All had negative microbiological samples. A granulomatous prostatitis was found among the patient with lung infiltration, but apart from its acute episode. All patients received empiric antibiotic therapy, fluoroquinolones in two and 3GC in three patients. Resolution of symptoms was noted in all the cases after a median time of 7 days (range 1–150 days). Discussion Complications of intravesical BCG therapy may harbor different clinical aspects and have various degrees of severity, sometimes leading to acute disease and death. Their diagnosis may be difficult and is usually retained after ruling out other causes, such as acute infection, evolution of malignancy, or drug toxicity. Mechanisms remain poorly understood and highly controversial [8]. For some authors, complications of BCG therapy result from hypersensitivity with diffuse granulomatous reaction without isolation of M. bovis [22,23], while for others, they represent an infectious disease related to the dissemination of M. bovis, which can be isolated from the involved sites [20,24]. In the present study 22 cases of BCGitis occurred after intravesical BCG therapy. Histological examination often contributed to confirmation of the diagnosis, since 10 of the 14 biopsies (71%) demonstrated the presence of granuloma whereas only 2 cultures out of 28 samples (7%) were positive for M. bovis. PCR contributed less than histological examination since it was positive in only one of the five patients studied, although previous studies suggested that it may have a good diagnostic value [25]. It should be remarked that 14 samples for microbiological examination and 3 samples for PCR detection were obtained after the introduction of fluoroquinolone, known for its efficiency against M. bovis [26], which could lead to a negative result. These data underline the predominant role of the hypersensitivity reaction, but suggest the existence of a mixed mechanism, as previously reported in the literature [27]. However, it should be underlined that there is no definition for ‘BCG therapy complication’; thus, the definition we used, like other definitions, might also lack sensitivity and specificity.
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The fact that all patients were male may be related to both the higher prevalence of bladder cancer in men [28] and the increased risk of traumatic catheterization compared with females, known to be a promoting factor for BCGitis [11–13]. It has to be stressed that in previous series, patients with BCG therapy complications [20,29] were also men only, whereas in other reports the gender of injured patients was not mentioned [12,14]. Both local (orchitis, granulomatous prostatitis, testicular abscess) and disseminated (miliary lung, hepatitis, arthritis, renal failure) complications were observed, in agreement with the classification described in the literature [13,30,31]. Systemic acute sepsis with hypotension was reported in six patients (27%). This incidence is probably overestimated since we studied patients for which the advice from an infectious disease specialist was required, thus selecting a higher proportion of subjects with a severe disease. Lamm et al. [12] reported a frequency of 5% of major complications after intravesical BCG therapy and 0.4% of systemic septic reaction. This is in agreement with Brausi et al. [14], whose data reported 0.3% of sepsis reaction. All the severe reactions occurred less than 24 h after instillation of BCG, as previously reported [20]. In addition, we noticed in the present study that severe reactions seem to occur earlier than mild reactions in the BCG therapy cycle (median of 3 instillations versus 6). The treatment of BCGitis depends on the clinical presentation; its modalities [31–33] have not been clearly defined. The European Association of Urology recommends [13] treating the patients for 6 months with a combination of three antituberculous drugs (rifampicin, isoniazid, and ethambutol), in association with high-dose corticosteroids in case of severe systemic reaction. Disseminated BCGitis without vascular collapsus, or persistent locoregional disease have to be referred to an infectious disease specialist and are usually treated either with fluoroquinolones at high dose, for an unknown period of time, and/or a dual therapy with isoniazid and rifampicin for 3 months, initially combined with corticosteroids. These recommendations are not based on prospective trials, but only on experimental studies. Indeed, in an experimental murine model of infection [26,27,34], the combination of rifampicin and isoniazid increases the survival of mice infected with intraperitoneal BCG compared with the control group [27,34]. Durek et al. [26] showed a good efficacy of fluoroquinolones (levofloxacin or ciprofloxacin) as monotherapy in this model. In the present study, the diversity of treatment regimens reflects the lack of consensual therapeutic approach, particularly
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about the treatment duration that mimics tuberculosis treatment regimens without any prospective study. The delay before the initiation of treatment was sometimes long (1–30 days), but combination of antituberculous drugs was often preceded by the administration of a fluoroquinolone (n 5). It has to be stressed that the natural resistance of BCG to pyrazinamide precludes the use of this drug. In the present study, it was used in three patients, before infectious disease specialist advice in two cases and because of the fears of tuberculosis reactivation in one case. The value of corticosteroids during BCGitis remains to be determined [13]. In a murine model, when administered in combination with dual therapy with rifampicin and isoniazid, corticosteroids increased survival in comparison with antituberculosis drugs alone [32,34]. However, it has to be noted that corticosteroids used alone in experimental infections are deleterious, with a lower survival rate than in the control group [34]. In the present study, all severe cases were treated with antituberculosis drugs associated with corticosteroid therapy. Improvement seemed to be more rapidly achieved in patients receiving corticosteroids even though their clinical picture was more severe. These data support the use of corticosteroids in combination with antituberculosis drugs, at least in severe cases, and also suggest the existence of a mixed mechanism previously described. The present study is hampered by several limits. First, this was a retrospective observational study of patients selected from an infectious diseases department and not from a urological department. Thus, only complications requiring infectious disease specialist opinion have been taken into account and the data do not reflect all the different clinical presentations of BCGitis. Second, the incidence of BCGitis could not be assessed. Then, information was missing regarding the unitary dose of BCG administered during each instillation and the traumatic nature of urinary polls, known to favor BCGitis, although a recent study did not find the predisposing role of this factor [14]. Finally, complications that might occur beyond the first year after the end of BCG treatment were not investigated In conclusion, complications of BCG therapy or BCGitis have various clinical presentations, being sometimes severe with systemic septic reactions and vascular collapsus potentially lethal. The diagnosis remains difficult and histological examination seems to be more efficient than microbiology. Indications for discontinuation of intravesical BCG therapy should be better established. Antituberculous drugs during BCGitis are effective but their modalities and indications have to be clarified, as well as the interest
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of fluoroquinolones. Corticosteroids seem to be effective when combined with antituberculosis drugs to reduce the duration of symptoms. Prospective trials with regimens containing fewer molecules and/ or a shorter duration of treatment are warranted. Acknowledgment
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We wanted to specially thank Helene Rossignol who helped us with the data collection. We are indebted to Pr Tonnel for his advice. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180. [2] Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Compérat E, et al. European Association of Urology. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;64:639–53. [3] Lamm DL. Advances in the treatment of superficial bladder cancer: optimizing BCG immunotherapy. Introduction. Eur Urol 1995;27(Suppl 1):1. [4] Lamm DL. Comparison of BCG with other intravesical agents. Urology 1991;37(Suppl 5):30–2. [5] Lamm DL. Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer. Clin Infect Dis 2000;31(Suppl 3):86–90. [6] Chopin DK, Gattegno B. Descriptive epidemiology of superficial bladder tumors. Prog Urol 2001;11:955–60. [7] Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J, et al. EAU guidelines on non-muscleinvasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011;59:997–1008. [8] Pfister C, Roupret M, Wallerand H, Davin JL, Quintens H, Guy L, et al. Recommandations en onco-urologie 2010: tumeurs urothéliales. Prog Urol 2010;20:255–74. [9] Prescott S, Jackson AM, Hawkyard SJ, Alexandroff AB, James K. Mechanisms of action of intravesical bacille Calmette-Guerin: local immune mechanisms. Clin Infect Dis 2000;31(Suppl 3):91–3. [10] Wittes RC. Immunology of bacille Calmette-Guerin and related topics. Clin Infect Dis 2000;31(Suppl 3):S59–63. [11] Debois H, Loupi E, Saliou P. Suivi de la tolérance de la BCG thérapie endovésicale en France: analyse quantitative des évènements indésirables graves notifiés sur cinq ans. Prog Urol 2001;12:604–8. [12] Lamm DL. Complications of bacillus Calmette-Guerin immunotherapy. Urol Clin North Am 1992;19:565–72. [13] Witjes JA, Palou J, Soloway M, Lamm D, Brausi M, Spermon JR, et al. Clinical practice recommendations for the prevention and management of intravesical therapy-associated adverse events. Eur Urol Suppl 2008;7:667–74. [14] Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, et al. 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;65:69–76. [15] Le Cam Y, Beuscart C, Le Moal S, Bousser J, Zimbacca F. Septicémie à BCG: une complication grave de la BCGthérapie intravésicale. Med Mal Infect 1999;29:483–6. [16] Fradet V, Gaudreau C, Perrotte P, Côté J, Paquin J-M. Management of hepatic granulomatous tuberculosis complicating intravesical BCG for superficial bladder cancer. Can Urol Assoc J 2007;1:269. [17] Álvarez-Múgica M, Gómez JMF, Vázquez VB, Monzón AJ, Rodríguez JMF, 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;3:7323. [18] Hellinger WC, Oldenburg WA, Alvarez S. Vascular and other serious infections with Mycobacterium bovis after bacillus of Calmette-Guerin therapy for bladder cancer. South Med J 1995;88:1212–16. [19] Viallard JF, Denis D, Texier-Maugein J, Parrens M, Faure I, Pellegrin JL, et al. Disseminated infection after bacille Calmette-Guerin instillation for treatment of bladder carcinoma. Clin Infect Dis 1999;29:451–2. [20] Gonzalez OY, Musher DM, Brar I, Furgeson S, Boktour MR, Septimus EJ, et al. Spectrum of bacille Calmette-Guérin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis 2003;36:140–8. [21] Sfaxi M, Langar H, Ouni A, Riahi Y, El Aidli S, Daghfous R, et al. Systemic BCG reactions after intravesical BCG therapy. A report of four cases. Therapie 2008;63:43–7. [22] Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 29-1998. A 57-year-old man with fever and jaundice after intravesical instillation of bacille Calmette-Guérin for bladder cancer. N Engl J Med 1998;339:831–7. [23] Elkabani M, Greene JN, Vincent AL, VanHook S, Sandin RL. Disseminated Mycobacterium bovis after intravesicular bacillus Calmette-Guerin treatments for bladder cancer. Cancer Control 2000;7:476–81. [24] Mcparland C, Cotton DJ, Gowda KS, Hoeppner VH, Martin WT, Weckworth PF. Miliary Mycobacterium bovis induced by intravesical bacille Calmette-Guérin immunotherapy. Am Rev Respir Dis 1992;146:1330–3. [25] Tuncer S, Tekin MI, Ozen H, Bilen C, Unal S, Remzi D. Detection of bacillus Calmette-Guerin in the blood by the polymerase chain reaction method of treated bladder cancer patients. J Urol 1997;158:2109–12. [26] Durek C, Jurczok A, Werner H, Jocham D, Böhle A. Optimal treatment of systemic Bacillus Calmette-Guerin infection: investigations in an animal model. J Urol 2002;168: 826–31. [27] Koukol SC, DeHaven JI, Riggs DR, Lamm DL. Drug therapy of bacillus Calmette-Guérin sepsis. Urol Res 1995; 22:373–6. [28] Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 2007;12:20–37. [29] Strock V, Dotevall L, Sandberg T, Gustafsson CK, Holmang S. Late bacilli. Calmette-Guerin infection with a large focal urinary bladder ulceration as a complication of bladder cancer treatment. BJU Int 2011;107:1592–7. [30] Saint F. Prévention et traitement des effets indésirables associés aux instillations endo-vésicales de BCG. Prog Urol 2006;16:780–5.
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[31] Saint F, Salomon L, Quintela A, Cicco A, Abbou CC, Chopin DK. Classification, favorising factors, prevention and treatment of side effects associated to bacillus CalmetteGuerin in treatment of superficial bladder tumors. Ann Urol 2002;36:120–31. [32] 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
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therapy in superficial bladder cancer. J Urol 1992;147: 596–600. [33] Rischmann P, Desgrandchamps F, Malavaud B, Chopin DK. BCG intravesical instillations: recommendations for sideeffects management. Eur Urol 2000;37(Suppl 1):33–6. [34] DeHaven JI, Traynellis C, Riggs DR, Ting E, Lamm DL. Antibiotic and steroid therapy of massive systemic bacillus Calmette-Guerin toxicity. J Urol 1992;147:738–42.
Original Article
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Complications following intravesical bacillus Calmette-Guerin treatment for bladder cancer: a case series of 22 patients J.D. Pommier1, N. Ben Lasfar1, N. Van Grunderbeeck2, C. Burdet3,4, C. LaouÉnan3,4,5, C. Rioux1, C. Pierre-Audigier6, A. Meybeck7, L. Choudat8, A. Benchikh5,9, S. Nguyen10, E. Bouvet1,5, P. Yeni1,4,5, Y. Yazdanpanah1,4,5 & V. Joly1,4 1Infectious
and Tropical Diseases Department, Bichat Hospital, AP-HP, Paris, 2Intermediate and Intensive Care Units, Hospital Center, Lens, 3Biostatistics Department, Bichat Hospital, AP-HP, Paris, 4IAME, UMR 1137, INSERM, Paris, 5Paris Diderot University, Sorbonne Paris Cité, Paris, 6Microbiology Department, Bichat Hospital, AP-HP, Paris, 7Intensive Care Unit, Hospital Center, Tourcoing, 8Pathology Department, Bichat Hospital, AP-HP, Paris, 9Urology Department, Bichat Hospital, AP-HP, Paris, and 10Infectious Disease Department, Hospital Center, Tourcoing, France
Abstract Background: Intravesical bacillus Calmette-Guerin (BCG) therapy is an effective and widely used treatment for superficial bladder carcinoma. Local complications are frequent whereas systemic complications are rare but can be serious, and their management is not well known. Methods: We describe retrospectively the records of 22 patients treated in 3 infectious disease departments, for complications related to intravesical BCG therapy as treatment of bladder cancer. Results: All the patients were male, with a median age of 68 years (range 56–88). Complications occurred after a median of 5 instillations (range 1–11) and were observed within 24 h following BCG instillation for 14 patients. Common symptoms were fever (n 20), impaired general condition (n 14), and shortness of breath (n 7). Six patients had a systemic septic reaction leading to transfer into the intensive care unit for five of them. Lung infiltration was the most frequent presentation (n 11). Mycobacterium bovis was isolated from only two patients, but histology showed the presence of a granuloma in nine patients. Antimycobacterial treatment was initialized in 17 patients; the outcome was favorable in 16 patients, with a median length of symptoms resolution of 22.5 days (range 5–425 days). Eleven patients received corticosteroids in addition to specific treatment and had a more rapid improvement. One patient died with disseminated BCGitis proved by biopsy. Conclusions: Complications following intravesical BCG therapy are rare but can be severe and fatal. Histology seems to be the method that contributes most in confirmation of the diagnosis. Antimycobacterial therapy is effective, and probably more efficient when combined with corticosteroids, but the regimen and duration of the treatment are not standardized.
Keywords: BCG; bladder cancer; intravesical instillation; Mycobacterium bovis
Introduction Bacillus Calmette-Guerin (BCG) is commonly used as a vaccine to prevent tuberculosis. It is also used as an intravesical immunotherapy to treat superficial bladder cancer [1,2]. Several reports have described its efficacy as an alternative to chemotherapy [3–5], making it currently the gold standard in the treatment of urothelial carcinoma of the bladder with intermediate or high risk of progression and recurrence, in case of no muscle involvement [2,6,7].
However, the optimal number and frequency of repeated injections of BCG are not well defined [8]. BCG is a live attenuated strain of Mycobacterium bovis supposed to interact locally with the immune system after intravesical injection, leading to cellmediated immunity targeting bladder cancer [9,10]. Complications that occur after intravesical BCG therapy are mostly local reactions such as cystitis and hematuria [11–13]. A review of 2602 patients receiving intravesical BCG therapy reported major adverse
Correspondence: Jean-David Pommier, Services des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, 46 Rue Henri Huchard, 75018 Paris, France. Tel: 33 6 88438181. E-mail: [email protected] (Received 6 February 2015; accepted 25 May 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1055794
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events in less than 5% of patients [12]. More recently systemic side effects were reported to occur in 30% of 1316 patients, including fever in 10% [14]. The main complications are granulomatous prostatitis, pneumonitis, and hepatitis, as well as systemic septic reactions. Systemic septic reaction can sometimes lead to death [15]. The diagnosis of adverse events may be difficult due to the lack of precise diagnosis criteria and the infrequent isolation of M. bovis. Many clinical cases have been reported [16–19] but few series are available [20,21]. To our knowledge, the most important series was reported in 2003 [20], describing the clinical presentation in eight patients. More accurate diagnostic criteria for complications of intravesical BCG therapy (BCGitis) would allow clinicians to optimize their management and would in particular be helpful to define the situations in which BCG therapy has to be interrupted. The aim of this retrospective study was: (i) to describe the clinical and biological characteristics of patients with major complications following intravesical BCG therapy for urothelial cancer; (ii) to describe the management of these patients; and (iii) to describe the evolution of complications following intravesical BCG therapy.
Materials and Methods We retrospectively studied records of patients who had been referred to an infectious disease department for BCGitis after intravesical instillation of BCG, performed for the treatment of biopsy-proved bladder cancer. Patients came from three large centers, the Infectious Disease Department of the university hospitals of Lille and Tourcoing (from January 1999 to December 2006) and the Infectious and Tropical Disease Department of BichatClaude Bernard Hospital, a university hospital in Paris (from January 2007 to December 2011). Complications were assessed during the year following intravesical BCG therapy. BCGitis was defined as: the occurrence of fever ( 38°C) without any other etiology, lasting more than 48 h, and/or at least one organ involvement other than the bladder, that led to discontinuation of BCG therapy. The diagnosis of organ involvement was based on clinical, biological, and radiological abnormalities. Among organ involvements, lung injury was defined as a radiological lung infiltrates and liver involvement was defined as an increase in alkaline phosphatase and gamma glutamine transferase (GGT) or in alanine and/or aspartate aminotransferases (ALT or AST) 1.5 times the upper limit of normal (ULN).
Cases were included whether or not there was a microbiological identification of M. bovis by culture, polymerase chain reaction (PCR) or histological confirmation (granulomas, with or without caseous necrosis). We distinguished local reactions limited to the genito-urinary tract and systemic reactions involving at least one site other than the genito-urinary tract. Severe systemic reactions were defined by the occurrence of septic shock syndrome. Results were expressed as absolute number and percentage for categorical variables, and median and range for continuous quantitative variables.
Results We report 22 cases of BCGitis after intravesical BCG therapy, 11 from the Lille and Tourcoing hospitals and 11 from Bichat Claude Bernard hospital.
Clinical characteristics The patients were all male, with a median age of 68 years (range 56–88 years). There was a history of Crohn’s disease, tuberculosis, and diabetes for one, two, and four patients, respectively. Other comorbidities included hypertension (n 7), coronary artery disease (n 3), and chronic obstructive pulmonary disease (COPD) (n 1). No patient was receiving steroids or immunosuppressive therapy at the time of BCG therapy. According to TNM grading (WHO 1973) and staging of urothelial carcinoma, tumors were classified as G1pTa (n 2), G2pTa (n 3), G3pTa (n 5), G2pT1 (n 1), or G3pT1 (n 6). Pathological findings were unknown in six cases. All complications occurred between the first and the eleventh instillations, after a median of 5 instillations. Severe reactions occurred earlier in the BCG therapy cycle (median of 3 instillations instead of 6). In 14 cases, complications were observed in the first 24 h after instillation; in the remaining cases, the median delay of occurrence was 13.5 days (range 3–19 days). The most common symptoms were fever 38°C (n 20, 91%), impaired general condition (n 14, 64%), and shortness of breath (n 7, 31%). The other symptoms are detailed in Table I. Two patients had only local complications, 1 had isolated fever, 16 had disseminated reactions, and 3 had local and disseminated complications. Organ involvement was almost constant (n 21) and often multiple (n 15, 77%). Six patients (27%) had a systemic septic reaction with hypotension, including five patients with multiorgan failure needing transfer into an intensive
Complications following intravesical BCG Biological characteristics
Table I. Clinical characteristics of the 22 patients. No. of patients (%)
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Characteristics Symptoms Fever Impaired general condition Shortness of breath Hypotension Urinary disorders Sweats Arthralgia Cough Conjunctivitis Organ involvement Disseminated Lung infiltration With hypoxemia Hepatitis Renal failure (creatininemia 120 mmol/L) Heart involvement Arthritis Vertebral osteomyelitis Pancreatic abscess Psoas abscess Locoregional Orchiepididymitis Granulomatous prostatitis Glans involvement Distribution of patients according to organ involvement Lung infiltration only Lung infiltration and other organ involvement Organ involvement without lung involvement Isolated fever
20 14 7 6 5 4 3 3 2
(91) (64) (32) (27) (23) (18) (14) (14) (9)
Abnormal white blood cell counts occurred in seven patients ( 12 000/ml among two patients and 4000/ml among five patients) and abnormal platelet counts ( 150 000/ml) in five patients (including 50 000 /ml in two patients). C-reactive protein (CRP) level was available for 16 patients and was always increased, with a median of 83 mg/L (range 12–296). Renal insufficiency with creatininemia 120 mmol/L occurred in nine patients (41%). Microbiological and histological characteristics
11 4 13 9 2 2 1 1 1
(50) (36) (59) (41) (9) (9) (5) (5) (5)
3 (14) 1 (5) 1 (5)
1 10 10 1
(5) (46) (46) (5)
care unit. Among these six patients, symptoms occurred in the 24 h following the instillation after a median of 3 instillations (range 2–11).
Twenty-eight microbiological samples were obtained from 17 patients (77%). Three patients had a positive acid-fast bacilli (AFB) smear, including two subjects with a positive culture for M. bovis. PCR was positive in only one of the five patients tested. This positive PCR was obtained from a bone marrow sample, while culture and direct examination were negative for mycobacteria. Biopsy was contributive in 9 of 10 patients, showing epithelioïd granuloma without caseous necrosis in 7 patients and with necrosis in 2 patients. Only one patient had both a positive culture for M. bovis and a granuloma on a vertebral sample. Details of microbiological and histology characteristics are summarized in Table II. Treatment and evolution Antibiotics were introduced in 12 patients (55%) while the diagnosis of BCGitis was pending.
Table II. Results of bacteriological and histological analysis. Bacteriology Sputum Bronchoalveolar lavage Tracheal aspiration Urine Joint liquid CSF Bone marrow Others Histology Lung Bronchial Transbronchial Post mortem Liver Prostate Testicles Vertebra Kidney Glans
3
No. of samples studied
AFB-positive (no. of samples)
Culture positive for M.bovis (no. of samples)
7 2 3 6 3 2 2 3
0 0 0 1 1 0 1 0
0 0 0 0 1 0 1 0
No. of samples studied
Non-caseous granuloma (no. of samples)
Caseous granuloma (no. of samples)
6 4 1 1 3 1 1 1 1 1
3 1 1 1 3 1 0 1 0 0
0 0 0 0 0 0 1 0 0 1
AFB, acid-fast bacilli; CSF, cerebrospinal fluid.
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Third-generation cephalosporins (3GC) (n 8, 67%) and fluoroquinolones (n 7, 58%) were the most frequently used antibiotics. Antituberculous drugs were initiated in 17 patients (77%). The majority of them (n 16) had a disseminated BCGitis; the remaining patient had a testicular nodule, in which histological examination revealed a granuloma that did not resolve spontaneously. Most of the patients with a microbiologically or histologically confirmed diagnosis were treated (n 10, 91%). The types of drugs used are described in Table III. The delay before initiation of antituberculosis drugs was variable, with a median of 12 days (range 1–90 days) after the onset of symptoms, two patients being treated as soon as the first day of symptoms. Treatment was prescribed with a median length of 6 months (range 0.75–16 months) for rifampicin and isoniazid and of 2 months (range 2–3 months) for ethambutol. Corticosteroids were associated with the initial phase of antituberculosis treatment in 65% of cases (n 11), including all patients with a severe systemic reaction. The median duration of corticotherapy was 8 weeks (range 1–16 weeks). The outcome was favorable in 95% of cases (n 21). Fever resolved after a median of 6 days (range 0–7 days) of therapy. The median length of hospital duration and symptoms resolution after the introduction of antituberculosis treatment was 15.0 (range 1–60) days and 22.5 days (range 5–425), respectively. Symptoms resolved more rapidly when corticosteroids were added, i.e. 15 days (range 5–44) instead of 105 days (range 11–425). One patient died after a systemic severe reaction with multiorgan failure while the treatment was started the first day Table III. Therapeutic regimens. Regimen Antituberculous drugs H HR HRE HREZ Corticosteroid therapy Combined with antituberculous drugs Isolated Antibiotics other than antituberculous drugs Without antituberculous drugs Fluoroquinolones Othersa Before treatment with antituberculous drugs Fluoroquinolones Othersa
No. of patients (%) 2 2 10 3
(9) (9) (45) (14)
11 0 12 5 2 3 7 5 2
(65) (0) (55) (23) (9) (14) (32) (23) (9)
E, ethambutol; H, isoniazid; R, rifampicin; Z, pyrazinamide. Antituberculosis drugs were given at usual dosages: H, 3–5 mg/kg; R, 10 mg/kg; E, 20 mg/kg. aAntibiotics without activity against M.bovis.
with antituberculosis drugs and corticosteroids. Postmortem histology revealed pulmonary and hepatic granulomas without necrosis. Five patients did not receive antituberculosis drugs, antibiotics or corticosteroids. All of them had fever, three had disseminated reaction: one had lung infiltration and two had hepatitis; one had only locoregional reaction and one had isolated fever. The median time of onset of symptoms was 1 day (range 1–42 days). All had negative microbiological samples. A granulomatous prostatitis was found among the patient with lung infiltration, but apart from its acute episode. All patients received empiric antibiotic therapy, fluoroquinolones in two and 3GC in three patients. Resolution of symptoms was noted in all the cases after a median time of 7 days (range 1–150 days). Discussion Complications of intravesical BCG therapy may harbor different clinical aspects and have various degrees of severity, sometimes leading to acute disease and death. Their diagnosis may be difficult and is usually retained after ruling out other causes, such as acute infection, evolution of malignancy, or drug toxicity. Mechanisms remain poorly understood and highly controversial [8]. For some authors, complications of BCG therapy result from hypersensitivity with diffuse granulomatous reaction without isolation of M. bovis [22,23], while for others, they represent an infectious disease related to the dissemination of M. bovis, which can be isolated from the involved sites [20,24]. In the present study 22 cases of BCGitis occurred after intravesical BCG therapy. Histological examination often contributed to confirmation of the diagnosis, since 10 of the 14 biopsies (71%) demonstrated the presence of granuloma whereas only 2 cultures out of 28 samples (7%) were positive for M. bovis. PCR contributed less than histological examination since it was positive in only one of the five patients studied, although previous studies suggested that it may have a good diagnostic value [25]. It should be remarked that 14 samples for microbiological examination and 3 samples for PCR detection were obtained after the introduction of fluoroquinolone, known for its efficiency against M. bovis [26], which could lead to a negative result. These data underline the predominant role of the hypersensitivity reaction, but suggest the existence of a mixed mechanism, as previously reported in the literature [27]. However, it should be underlined that there is no definition for ‘BCG therapy complication’; thus, the definition we used, like other definitions, might also lack sensitivity and specificity.
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The fact that all patients were male may be related to both the higher prevalence of bladder cancer in men [28] and the increased risk of traumatic catheterization compared with females, known to be a promoting factor for BCGitis [11–13]. It has to be stressed that in previous series, patients with BCG therapy complications [20,29] were also men only, whereas in other reports the gender of injured patients was not mentioned [12,14]. Both local (orchitis, granulomatous prostatitis, testicular abscess) and disseminated (miliary lung, hepatitis, arthritis, renal failure) complications were observed, in agreement with the classification described in the literature [13,30,31]. Systemic acute sepsis with hypotension was reported in six patients (27%). This incidence is probably overestimated since we studied patients for which the advice from an infectious disease specialist was required, thus selecting a higher proportion of subjects with a severe disease. Lamm et al. [12] reported a frequency of 5% of major complications after intravesical BCG therapy and 0.4% of systemic septic reaction. This is in agreement with Brausi et al. [14], whose data reported 0.3% of sepsis reaction. All the severe reactions occurred less than 24 h after instillation of BCG, as previously reported [20]. In addition, we noticed in the present study that severe reactions seem to occur earlier than mild reactions in the BCG therapy cycle (median of 3 instillations versus 6). The treatment of BCGitis depends on the clinical presentation; its modalities [31–33] have not been clearly defined. The European Association of Urology recommends [13] treating the patients for 6 months with a combination of three antituberculous drugs (rifampicin, isoniazid, and ethambutol), in association with high-dose corticosteroids in case of severe systemic reaction. Disseminated BCGitis without vascular collapsus, or persistent locoregional disease have to be referred to an infectious disease specialist and are usually treated either with fluoroquinolones at high dose, for an unknown period of time, and/or a dual therapy with isoniazid and rifampicin for 3 months, initially combined with corticosteroids. These recommendations are not based on prospective trials, but only on experimental studies. Indeed, in an experimental murine model of infection [26,27,34], the combination of rifampicin and isoniazid increases the survival of mice infected with intraperitoneal BCG compared with the control group [27,34]. Durek et al. [26] showed a good efficacy of fluoroquinolones (levofloxacin or ciprofloxacin) as monotherapy in this model. In the present study, the diversity of treatment regimens reflects the lack of consensual therapeutic approach, particularly
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about the treatment duration that mimics tuberculosis treatment regimens without any prospective study. The delay before the initiation of treatment was sometimes long (1–30 days), but combination of antituberculous drugs was often preceded by the administration of a fluoroquinolone (n 5). It has to be stressed that the natural resistance of BCG to pyrazinamide precludes the use of this drug. In the present study, it was used in three patients, before infectious disease specialist advice in two cases and because of the fears of tuberculosis reactivation in one case. The value of corticosteroids during BCGitis remains to be determined [13]. In a murine model, when administered in combination with dual therapy with rifampicin and isoniazid, corticosteroids increased survival in comparison with antituberculosis drugs alone [32,34]. However, it has to be noted that corticosteroids used alone in experimental infections are deleterious, with a lower survival rate than in the control group [34]. In the present study, all severe cases were treated with antituberculosis drugs associated with corticosteroid therapy. Improvement seemed to be more rapidly achieved in patients receiving corticosteroids even though their clinical picture was more severe. These data support the use of corticosteroids in combination with antituberculosis drugs, at least in severe cases, and also suggest the existence of a mixed mechanism previously described. The present study is hampered by several limits. First, this was a retrospective observational study of patients selected from an infectious diseases department and not from a urological department. Thus, only complications requiring infectious disease specialist opinion have been taken into account and the data do not reflect all the different clinical presentations of BCGitis. Second, the incidence of BCGitis could not be assessed. Then, information was missing regarding the unitary dose of BCG administered during each instillation and the traumatic nature of urinary polls, known to favor BCGitis, although a recent study did not find the predisposing role of this factor [14]. Finally, complications that might occur beyond the first year after the end of BCG treatment were not investigated In conclusion, complications of BCG therapy or BCGitis have various clinical presentations, being sometimes severe with systemic septic reactions and vascular collapsus potentially lethal. The diagnosis remains difficult and histological examination seems to be more efficient than microbiology. Indications for discontinuation of intravesical BCG therapy should be better established. Antituberculous drugs during BCGitis are effective but their modalities and indications have to be clarified, as well as the interest
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of fluoroquinolones. Corticosteroids seem to be effective when combined with antituberculosis drugs to reduce the duration of symptoms. Prospective trials with regimens containing fewer molecules and/ or a shorter duration of treatment are warranted. Acknowledgment
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We wanted to specially thank Helene Rossignol who helped us with the data collection. We are indebted to Pr Tonnel for his advice. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180. [2] Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Compérat E, et al. European Association of Urology. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;64:639–53. [3] Lamm DL. Advances in the treatment of superficial bladder cancer: optimizing BCG immunotherapy. Introduction. Eur Urol 1995;27(Suppl 1):1. [4] Lamm DL. Comparison of BCG with other intravesical agents. Urology 1991;37(Suppl 5):30–2. [5] Lamm DL. Efficacy and safety of bacille Calmette-Guerin immunotherapy in superficial bladder cancer. Clin Infect Dis 2000;31(Suppl 3):86–90. [6] Chopin DK, Gattegno B. Descriptive epidemiology of superficial bladder tumors. Prog Urol 2001;11:955–60. [7] Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J, et al. EAU guidelines on non-muscleinvasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011;59:997–1008. [8] Pfister C, Roupret M, Wallerand H, Davin JL, Quintens H, Guy L, et al. Recommandations en onco-urologie 2010: tumeurs urothéliales. Prog Urol 2010;20:255–74. [9] Prescott S, Jackson AM, Hawkyard SJ, Alexandroff AB, James K. Mechanisms of action of intravesical bacille Calmette-Guerin: local immune mechanisms. Clin Infect Dis 2000;31(Suppl 3):91–3. [10] Wittes RC. Immunology of bacille Calmette-Guerin and related topics. Clin Infect Dis 2000;31(Suppl 3):S59–63. [11] Debois H, Loupi E, Saliou P. Suivi de la tolérance de la BCG thérapie endovésicale en France: analyse quantitative des évènements indésirables graves notifiés sur cinq ans. Prog Urol 2001;12:604–8. [12] Lamm DL. Complications of bacillus Calmette-Guerin immunotherapy. Urol Clin North Am 1992;19:565–72. [13] Witjes JA, Palou J, Soloway M, Lamm D, Brausi M, Spermon JR, et al. Clinical practice recommendations for the prevention and management of intravesical therapy-associated adverse events. Eur Urol Suppl 2008;7:667–74. [14] Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta,
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[31] Saint F, Salomon L, Quintela A, Cicco A, Abbou CC, Chopin DK. Classification, favorising factors, prevention and treatment of side effects associated to bacillus CalmetteGuerin in treatment of superficial bladder tumors. Ann Urol 2002;36:120–31. [32] 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
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therapy in superficial bladder cancer. J Urol 1992;147: 596–600. [33] Rischmann P, Desgrandchamps F, Malavaud B, Chopin DK. BCG intravesical instillations: recommendations for sideeffects management. Eur Urol 2000;37(Suppl 1):33–6. [34] DeHaven JI, Traynellis C, Riggs DR, Ting E, Lamm DL. Antibiotic and steroid therapy of massive systemic bacillus Calmette-Guerin toxicity. J Urol 1992;147:738–42.
