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Corticosteroid-Associated Fatal Mycobacterial Sepsis Occurring 3 Years after Instillation of Intravesical Bacillus Calmette-Guerin
0022-534 7/93/1505-1498$03.00/0
Vol. 150, 1498-1500, November 1993
THE JOURNAL O F UROLOGY Copyright © 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U. S. A .
CORTICOSTEROID -ASSOCIATED FATAL MYCOBACTERIAL SEPSIS OCCURRING 3 YEARS AFTER INSTILLATION OF INTRAVESICAL BACILLUS CALMETTE-GUERIN JOSEPH K. IZES, WILLIAM BIHRLE, III*
AND
CHRISTINE B. THOMAS
From the Departments of Urology and Anatomic Pathology, Lahey Clinic, Burlington, Massachusetts
ABSTRACT
A case is reported of systemic Mycobacterium bovis infection that occurred 3 years after uneventful instillation of intravesical bacillus Calmette-Guerin (BCG) and after several months of oral prednisone therapy. The literature on delayed BCG infection and the systemic persistence of BCG after intravesical instillation is reviewed. We propose that rarely a reservoir of dormant M. bovis may become established after intravesical therapy. Reactivation infection may later develop in a manner that p arallels the natural history of secondary tuberculosis. KEY WORD S :
mycobacterium bovis, BCG vaccine, adrenal cortex hormone
Since the introduction of intravesical bacillus Calmette Guerin (BCG) therapy in 1976 by Morales et al, 1 it has become accepted as the most clinically effective intravesical agent available for the treatment of superficial transitional cell car cinoma of the bladder. This attenuated strain of Mycobacte rium bovis was developed at the Pasteur Institute more than 80 years ago as an immunoprophylactic against tuberculosis. More recently, the antineoplastic/immunoadjuvant properties of BCG against a variety of solid and hematopoietic malignant neoplasms have been well documented. 2 Intravesical instillation of BCG is usually associated with relatively few side effects. The incidence of BCG sepsis imme diately after intravesical instillation is reported at less than 1% in the largest series to date. 3 However, since that time several reports have described systemic BCG infection months or years after treatment. 4 -6 We report and discuss fatal mycobacterial sepsis that occurred after several months of steroid therapy in a patient who had been treated with intravesical BCG 3 years previously. C A S E REP ORT
A 69-year-old retired teacher, with a history of repair of an abdominal aortic aneurysm, presented with hematuria and was found to have multifocal grade I to II papillary transitional cell carcinoma (noninvasive) and carcinoma in situ of the bladder. A recurrent grade II superficial tumor was noted at 3-month followup cystoscopy. A course of 6 weekly instillations of in travesical BCG (Tice strain) was administered beginning 28 days after transurethral resection. These treatments were well tolerated and accompanied only by a sensation of mild urgency and frequency of urination that was self-limited. Subsequent cystoscopic examinations yielded negative results. During the next 2 years the patient was free of medical problems. Weakness and malaise subsequently developed, prompting laboratory evaluation. Levels of serum creatinine, which had previously been in the high normal range, were elevated at 8.4 mg./dl. (normal 0.6 to 1.2). A renal biopsy demonstrated tubulous interstitial nephritis with noncaseating granulomas. Stains for bacteria fungi and acid-fast bacilli were negative. The patient required dialysis acutely but renal func tion improved appreciably on a daily regimen of low dose oral prednisone. The overall condition appeared stable during the next 8 months. The patient underwent transurethral resection of the prostate that yielded benign tissue that was remarkable only for noncaseating granulomatous inflammation. Accepted for publication April 30, 1993. * Requests for reprints: Department of Urology, Lahey Clinic, 41 Mall Rd., Burlington, Massachusetts 01805.
The patient was admitted to the medical service 3 years after the initial presentation because of confusion, weight loss and severe fatigue. Physical examination was remarkable for cach exia and generalized weakness without focality. A mild upper extremity tremor, diminished lower extremity vibration sense and hyperreflexia were noted. The course evolved into a febrile/ septic syndrome with altered mental status. The condition was unresponsive to courses of multiple broad-spectrum antibiotics. Repeated cultures of blood, urine and sputum were negative for bacteria, fungi or acid-fast bacilli. Computerized tomography (CT) of the abdomen revealed an 8 cm. fluid-filled cavity that involved the left psoas muscle. Percutaneous drainage of the area yielded 500 cc of green opaque fluid with a white blood count of 190,000/mm. 3 (normal 3,200 to 9,800). Most of the cells appeared to be polymorphonuclear leukocytes. Cultures and stain for bacteria, fungi and acid-fast bacilli were negative. CT of the head and a lumbar puncture were unrevealing. CT of the chest and echocardiography were noncontributory except for a 5 cm. aneurysmal dilatation of the aortic root. An indium scan demonstrated increased uptake in an enlarged spleen. Results of Venereal Disease Research Laboratory and human immunodeficiency virus tests were negative. Subsequently, up per gastrointestinal bleeding developed secondary to stress gastritis. After 28 days of treatment the family requested com fort measures only and the patient died 9 days later. At autopsy a mycotic aneurysm of the aortic arch was present with formation of an abscess and adhesions to the left upper lobe of the lung, a para-aortic abscess was adjacent to the abdominal aneurysm repair and an abscess was present in the left testicle that extended into the epididymis. Microscopically, granulomatous inflammation with caseation was noted, with numerous acid-fast bacilli identified on special stains (see fig ure). In addition, granulomatous inflammation with positive stains for acid-fast bacilli was present in the kidney, prostate gland and bladder. The brain showed chronic tuberculous men ingitis. Histological demonstration of infection could not be shown in the lungs, liver or spleen. However, cultures from these organs as well as brain and abscess fluids were positive for M. bovis. DISCU S S I O N
Reactivation or late exacerbation of mycobacterial tubercu losis infection is a well described clinical entity in which pro gression of active infection recurs many years after primary infection. The reservoir of tubercle bacilli that is responsible for reactivation tuberculosis is believed to be a caseous resid uum in the lung, lymph nodes or other sites of hematogenous implantation of the resolved primary infection. 7 The coincident
1498
FATAL MYC OBACTERIAL SEP S I S AFTER IN STILLATIO N O F BACILLUS CALMETTE - GUERIN
1499
A , medium power section of abscess in left testicle shows numerous histiocytes in infiltrate with necrosis. Reduced from X250. B, numerous bacilli are seen under oil immersion on special stains for acid-fast organisms. Reduced from X l,000.
occurrence of reactivation with deteriorating general health or iatrogenic immunosuppression is well described. 8 To our knowl edge, no similar phenomenon has been described after treat ment with any of the attenuated strains of M. bovis known as ECG. Evidence exists of sporadic persistence of BCG locally and systemically in treated patients after intravesical therapy. Lage et al were able to demonstrate acid-fast bacilli in 1 of 39 patients who underwent biopsy 6 weeks after intravesical BCG treat ment.9 Granulomas containing acid-fast bacilli were removed from the bladder, prostate and epididymis 6 months after intravesical therapy. 10 Armstrong described the late develop ment of a chest wall nodule and caseating granulomas that contained viable M. bovis. 1 1 Interestingly, the literature on ECG-related fatalities con tains scattered reports that are consistent with the reactivation pattern of infection. 4-6• 1 2 Deresiewicz et al reported on a fatal disseminated mycobacterial infection that occurred 14 months after intravesical BCG was administered immediately after transurethral resection. 5 Of note, this patient had undergone a course of oral prednisone and a stressful surgical procedure before the fulminant septic course. BCG pneumonitis 14 months after a single instillation and 11 months after radical cystectomy has been described. 4 In a review of 5 instances of systemic infection after intravesical therapy Steg et al included a patient who had granulomatous hepatitis and BCG pneumo nitis 6 months after cessation of therapy. 6 A prominent feature of all of these cases and our own is the difficulty associated with isolating the bacillus from antemortem cultures. 1 2 Systemic BCG infection after intravesical administration occurred in 12 of 1,278 patients reviewed by Lamm et aL 3 Although in some patients this was clearly related to traumatic catheterization, others apparently had systemic exposure after routine intravesical instillation. Presumably, a small subset of these patients harbors the bacillus systemically. We propose that in these rare instances systemic foci of BCG may become established and persist for months or years after intravesical administration. The bacillus is inactive and dormant, in a manner similar to that of resolved primary tuberculosis infec tion, until some form of immune compromise occurs. This group may then be at risk for later development of secondary or reactivation BCG sepsis as illustrated by our case. Several potential reservoirs of infection existed in our case. Although BCG is usually considered rarely to affect the upper urinary tract even in the presence of reflux, 13 · 14 sporadic in stances of renal seeding have been described. 15 • 16 The presence of tubulous interstitial nephritis has been reported in 2 patients with signs of systemic BCG infection and renal insufficiency. 1 7 Although stains for acid-fast bacilli were negative in our pa-
tient, a distinct possibility exists that the renal dysfunction was actually secondary to active mycobacterial infection. The potentially catastrophic result of any immunosuppressive med ication in this setting must be considered. Delayed vascular M. bovis infection has been described in a few patients previously treated with BCG. Deresiewicz et al found evidence of acid-fast bacilli in an aneurysmal sac as well as colonization of a vascular graft. 5 Interestingly, these orga nisms were identifiable in tissue sections but they would not grow in culture. A mycotic abdominal aortic aneurysm that developed 30 months after intralesional injection of BCG for melanoma was reported by Woods et al. 1 8 The para-aortic graft abscess in our patient might suggest an endovascular reservoir infection. The development of a febrile illness of uncertain diagnosis in a patient with previous exposure to BCG, especially after surgical stress or the administration of imunosuppressant med ication, is highly suspicious for systemic BCG infection. The use of empiric antituberculous therapy should be strongly con sidered and should not be delayed to await definitive microbi ological confirmation. Immunosuppression should be ap proached with great caution in patients who were previously treated with BCG. The prophylactic use of antituberculous drugs, such as isoniazid, with systemic immunosuppression is not without justification. Most importantly, the patient and physician must remain aware of the slight possibility of late reactivation systemic infection. REFERENCES
1 . Morales, A.,Eidinger, D. and Bruce,A. W.: Intracavatory Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. UroL, l l 6 : 180, 1976. 2. Nathanson, L. : Use of BCG in the treatment of human neoplasms: a review. Sem. Oncol., 1: 337, 1974. 3. Lamm, D. L., Steg, A., Boccon-Gibod, L., Morales, A., Hanna, IVL G., Jr.,Pagano, F.,Alfthan, 0 . , Brosman, S., Fisher, H. A., Jakse, G., Chisholm, G. D., van der Meijden, A. P. M. and Debruyne, F. M. J.: Complications of bacillus Calmette-Guerin immuno therapy: review of 2,602 patients and comparison of chemother apy complications.Prog. Clin. Biol. Res., 310: 335, 1989. 4. Bohle, A., Kirsten, D., Schroder, K.-H., Knipper, A., Fornara, P., Magnussen, H. and Jocham, D.: Clinical evidence of systemic persistence of bacillus Calmette-Guerin: long-term pulmonary bacillusCalmette-Guerin infection after intravesical therapy for bladder cancer and subsequent cystectomy. J. Urol., 148: 1894, 1992. 5. Deresiewicz, R. L., Stone, R. M. andAster, J.C.: Fatal disseminated mycobacterial infection following intravesical bacillusCalmette Guerin. J. Urol., 144: 1331, 1 990. 6. Steg, A., Leleu, C., Debre, B., Boccon-Gibod, L. and Sicard, D.: Systemic bacillus Calmette-Guerin infection, "BCGitis," in pa-
1500 7.
8.
9.
10. 11. 12.
FATAL MYCOBACTERIAL SEPSIS AFTER INSTILLATIO N O F BACILLUS CALMETTE- GUERIN
tients treated by intravesical bacillus Calmette-Guerin therapy for bladder cancer. Eur. Urol., 16: 161, 1989. Harris, H. W.: Pulmonary tuberculosis. In: Infectious Diseases: A Modern Treatise of Infections Processes, 4th ed. Edited by P. D. Hoeprich and M. C. Jordan. Philadelphia: J. B. Lippincott Co., chapt. 37, pp. 422-423, 1989. Des Prez, R. M. and Heim, C. R.: Mycobacterium tuberculosis. In: Principles and Practice of Infectious Diseases, 3rd ed. Edited by G. L. Mandell, R. G. Douglas, Jr. and J. E. Bennett. New York: Churchill Livingstone, part III, chapt. 229, pp. 1878-1884, 1990. Lage, J. M., Bauer, W. C., Kelley, D. R., Ratliff, T. L. and Catalona, W. J.: Histological parameters and pitfalls in the interpretation of bladder biopsies in bacillus Calmette-Guerin treatment of superficial bladder cancer. J. Urol., 13 5 : 916, 1986. Linn, R., Klimberg, I. W. and Wajsman, Z.: Persistent acid-fast bacilli following intravesical bacillus Calmette-Guerin. J. Urol., 141: 1 197, 1989. Armstrong, R. W.: Complications after intravesical instillation of bacillus Calmette-Guerin: rhabdomyolysis and metastatic infec tion. J. Urol., 1 4 5 : 1264, 1991. Aungst, C. W., Sokal, J. E . and Jager, B. V.: Complications of BCG
13. 14. 15. 16. 17. 18.
vaccination in neoplastic disease. Ann. Intern. Med., 82: 666, 1975. Mukamel, E., Vilkovsky, E., Hadar, H., Engelstein, D., Nussbaum, B. and Servadio, C.: The effect of intravesical bacillus Calmette Guerin therapy on the upper urinary tract. J. Urol., 146: 980, 1991. Biihle, A., Schuller, J., Knipper, A. and Hofstetter, A.: Bacillus Calmette-Guerin treatment and vesicorenal reflux. Eur. Urol., 17: 125, 1990. Gonzalez, J. A., Marco!, B. R. and Wolf, M. C.: Complications of intravesical bacillus Calmette-Guerin: a case report. J. Urol. , 1 48: 1892, 1992. Stanisic, T. H., Brewer, M. L. and Graham, A. R.: Intravesical bacillus Calmette-Guerin therapy and associated granulomatous renal masses. J. Urol., 135: 356, 1986. Modesto, A., Marty, L., Sue, J.-M., Kleinknecht, D., de Fremont, J.-F., Marsepoil, T. and Veyssier, P.: Renal complications of intravesical bacillus Calmette-Guerin therapy. Amer. J. Ne phrol., 1 1 : 501, 1991. Woods, J. M., 4th, Schellack, J., Stewart, M. T., Murray, D. R. and Schwartzman, S. W.: Mycotic abdominal aortic aneurysm in duced by immunotherapy with bacille Calmette-Guerin vaccine for malignancy. J. Vase. Surg., 7: 808, 1988.
Vol. 150, 1498-1500, November 1993
THE JOURNAL O F UROLOGY Copyright © 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U. S. A .
CORTICOSTEROID -ASSOCIATED FATAL MYCOBACTERIAL SEPSIS OCCURRING 3 YEARS AFTER INSTILLATION OF INTRAVESICAL BACILLUS CALMETTE-GUERIN JOSEPH K. IZES, WILLIAM BIHRLE, III*
AND
CHRISTINE B. THOMAS
From the Departments of Urology and Anatomic Pathology, Lahey Clinic, Burlington, Massachusetts
ABSTRACT
A case is reported of systemic Mycobacterium bovis infection that occurred 3 years after uneventful instillation of intravesical bacillus Calmette-Guerin (BCG) and after several months of oral prednisone therapy. The literature on delayed BCG infection and the systemic persistence of BCG after intravesical instillation is reviewed. We propose that rarely a reservoir of dormant M. bovis may become established after intravesical therapy. Reactivation infection may later develop in a manner that p arallels the natural history of secondary tuberculosis. KEY WORD S :
mycobacterium bovis, BCG vaccine, adrenal cortex hormone
Since the introduction of intravesical bacillus Calmette Guerin (BCG) therapy in 1976 by Morales et al, 1 it has become accepted as the most clinically effective intravesical agent available for the treatment of superficial transitional cell car cinoma of the bladder. This attenuated strain of Mycobacte rium bovis was developed at the Pasteur Institute more than 80 years ago as an immunoprophylactic against tuberculosis. More recently, the antineoplastic/immunoadjuvant properties of BCG against a variety of solid and hematopoietic malignant neoplasms have been well documented. 2 Intravesical instillation of BCG is usually associated with relatively few side effects. The incidence of BCG sepsis imme diately after intravesical instillation is reported at less than 1% in the largest series to date. 3 However, since that time several reports have described systemic BCG infection months or years after treatment. 4 -6 We report and discuss fatal mycobacterial sepsis that occurred after several months of steroid therapy in a patient who had been treated with intravesical BCG 3 years previously. C A S E REP ORT
A 69-year-old retired teacher, with a history of repair of an abdominal aortic aneurysm, presented with hematuria and was found to have multifocal grade I to II papillary transitional cell carcinoma (noninvasive) and carcinoma in situ of the bladder. A recurrent grade II superficial tumor was noted at 3-month followup cystoscopy. A course of 6 weekly instillations of in travesical BCG (Tice strain) was administered beginning 28 days after transurethral resection. These treatments were well tolerated and accompanied only by a sensation of mild urgency and frequency of urination that was self-limited. Subsequent cystoscopic examinations yielded negative results. During the next 2 years the patient was free of medical problems. Weakness and malaise subsequently developed, prompting laboratory evaluation. Levels of serum creatinine, which had previously been in the high normal range, were elevated at 8.4 mg./dl. (normal 0.6 to 1.2). A renal biopsy demonstrated tubulous interstitial nephritis with noncaseating granulomas. Stains for bacteria fungi and acid-fast bacilli were negative. The patient required dialysis acutely but renal func tion improved appreciably on a daily regimen of low dose oral prednisone. The overall condition appeared stable during the next 8 months. The patient underwent transurethral resection of the prostate that yielded benign tissue that was remarkable only for noncaseating granulomatous inflammation. Accepted for publication April 30, 1993. * Requests for reprints: Department of Urology, Lahey Clinic, 41 Mall Rd., Burlington, Massachusetts 01805.
The patient was admitted to the medical service 3 years after the initial presentation because of confusion, weight loss and severe fatigue. Physical examination was remarkable for cach exia and generalized weakness without focality. A mild upper extremity tremor, diminished lower extremity vibration sense and hyperreflexia were noted. The course evolved into a febrile/ septic syndrome with altered mental status. The condition was unresponsive to courses of multiple broad-spectrum antibiotics. Repeated cultures of blood, urine and sputum were negative for bacteria, fungi or acid-fast bacilli. Computerized tomography (CT) of the abdomen revealed an 8 cm. fluid-filled cavity that involved the left psoas muscle. Percutaneous drainage of the area yielded 500 cc of green opaque fluid with a white blood count of 190,000/mm. 3 (normal 3,200 to 9,800). Most of the cells appeared to be polymorphonuclear leukocytes. Cultures and stain for bacteria, fungi and acid-fast bacilli were negative. CT of the head and a lumbar puncture were unrevealing. CT of the chest and echocardiography were noncontributory except for a 5 cm. aneurysmal dilatation of the aortic root. An indium scan demonstrated increased uptake in an enlarged spleen. Results of Venereal Disease Research Laboratory and human immunodeficiency virus tests were negative. Subsequently, up per gastrointestinal bleeding developed secondary to stress gastritis. After 28 days of treatment the family requested com fort measures only and the patient died 9 days later. At autopsy a mycotic aneurysm of the aortic arch was present with formation of an abscess and adhesions to the left upper lobe of the lung, a para-aortic abscess was adjacent to the abdominal aneurysm repair and an abscess was present in the left testicle that extended into the epididymis. Microscopically, granulomatous inflammation with caseation was noted, with numerous acid-fast bacilli identified on special stains (see fig ure). In addition, granulomatous inflammation with positive stains for acid-fast bacilli was present in the kidney, prostate gland and bladder. The brain showed chronic tuberculous men ingitis. Histological demonstration of infection could not be shown in the lungs, liver or spleen. However, cultures from these organs as well as brain and abscess fluids were positive for M. bovis. DISCU S S I O N
Reactivation or late exacerbation of mycobacterial tubercu losis infection is a well described clinical entity in which pro gression of active infection recurs many years after primary infection. The reservoir of tubercle bacilli that is responsible for reactivation tuberculosis is believed to be a caseous resid uum in the lung, lymph nodes or other sites of hematogenous implantation of the resolved primary infection. 7 The coincident
1498
FATAL MYC OBACTERIAL SEP S I S AFTER IN STILLATIO N O F BACILLUS CALMETTE - GUERIN
1499
A , medium power section of abscess in left testicle shows numerous histiocytes in infiltrate with necrosis. Reduced from X250. B, numerous bacilli are seen under oil immersion on special stains for acid-fast organisms. Reduced from X l,000.
occurrence of reactivation with deteriorating general health or iatrogenic immunosuppression is well described. 8 To our knowl edge, no similar phenomenon has been described after treat ment with any of the attenuated strains of M. bovis known as ECG. Evidence exists of sporadic persistence of BCG locally and systemically in treated patients after intravesical therapy. Lage et al were able to demonstrate acid-fast bacilli in 1 of 39 patients who underwent biopsy 6 weeks after intravesical BCG treat ment.9 Granulomas containing acid-fast bacilli were removed from the bladder, prostate and epididymis 6 months after intravesical therapy. 10 Armstrong described the late develop ment of a chest wall nodule and caseating granulomas that contained viable M. bovis. 1 1 Interestingly, the literature on ECG-related fatalities con tains scattered reports that are consistent with the reactivation pattern of infection. 4-6• 1 2 Deresiewicz et al reported on a fatal disseminated mycobacterial infection that occurred 14 months after intravesical BCG was administered immediately after transurethral resection. 5 Of note, this patient had undergone a course of oral prednisone and a stressful surgical procedure before the fulminant septic course. BCG pneumonitis 14 months after a single instillation and 11 months after radical cystectomy has been described. 4 In a review of 5 instances of systemic infection after intravesical therapy Steg et al included a patient who had granulomatous hepatitis and BCG pneumo nitis 6 months after cessation of therapy. 6 A prominent feature of all of these cases and our own is the difficulty associated with isolating the bacillus from antemortem cultures. 1 2 Systemic BCG infection after intravesical administration occurred in 12 of 1,278 patients reviewed by Lamm et aL 3 Although in some patients this was clearly related to traumatic catheterization, others apparently had systemic exposure after routine intravesical instillation. Presumably, a small subset of these patients harbors the bacillus systemically. We propose that in these rare instances systemic foci of BCG may become established and persist for months or years after intravesical administration. The bacillus is inactive and dormant, in a manner similar to that of resolved primary tuberculosis infec tion, until some form of immune compromise occurs. This group may then be at risk for later development of secondary or reactivation BCG sepsis as illustrated by our case. Several potential reservoirs of infection existed in our case. Although BCG is usually considered rarely to affect the upper urinary tract even in the presence of reflux, 13 · 14 sporadic in stances of renal seeding have been described. 15 • 16 The presence of tubulous interstitial nephritis has been reported in 2 patients with signs of systemic BCG infection and renal insufficiency. 1 7 Although stains for acid-fast bacilli were negative in our pa-
tient, a distinct possibility exists that the renal dysfunction was actually secondary to active mycobacterial infection. The potentially catastrophic result of any immunosuppressive med ication in this setting must be considered. Delayed vascular M. bovis infection has been described in a few patients previously treated with BCG. Deresiewicz et al found evidence of acid-fast bacilli in an aneurysmal sac as well as colonization of a vascular graft. 5 Interestingly, these orga nisms were identifiable in tissue sections but they would not grow in culture. A mycotic abdominal aortic aneurysm that developed 30 months after intralesional injection of BCG for melanoma was reported by Woods et al. 1 8 The para-aortic graft abscess in our patient might suggest an endovascular reservoir infection. The development of a febrile illness of uncertain diagnosis in a patient with previous exposure to BCG, especially after surgical stress or the administration of imunosuppressant med ication, is highly suspicious for systemic BCG infection. The use of empiric antituberculous therapy should be strongly con sidered and should not be delayed to await definitive microbi ological confirmation. Immunosuppression should be ap proached with great caution in patients who were previously treated with BCG. The prophylactic use of antituberculous drugs, such as isoniazid, with systemic immunosuppression is not without justification. Most importantly, the patient and physician must remain aware of the slight possibility of late reactivation systemic infection. REFERENCES
1 . Morales, A.,Eidinger, D. and Bruce,A. W.: Intracavatory Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. UroL, l l 6 : 180, 1976. 2. Nathanson, L. : Use of BCG in the treatment of human neoplasms: a review. Sem. Oncol., 1: 337, 1974. 3. Lamm, D. L., Steg, A., Boccon-Gibod, L., Morales, A., Hanna, IVL G., Jr.,Pagano, F.,Alfthan, 0 . , Brosman, S., Fisher, H. A., Jakse, G., Chisholm, G. D., van der Meijden, A. P. M. and Debruyne, F. M. J.: Complications of bacillus Calmette-Guerin immuno therapy: review of 2,602 patients and comparison of chemother apy complications.Prog. Clin. Biol. Res., 310: 335, 1989. 4. Bohle, A., Kirsten, D., Schroder, K.-H., Knipper, A., Fornara, P., Magnussen, H. and Jocham, D.: Clinical evidence of systemic persistence of bacillus Calmette-Guerin: long-term pulmonary bacillusCalmette-Guerin infection after intravesical therapy for bladder cancer and subsequent cystectomy. J. Urol., 148: 1894, 1992. 5. Deresiewicz, R. L., Stone, R. M. andAster, J.C.: Fatal disseminated mycobacterial infection following intravesical bacillusCalmette Guerin. J. Urol., 144: 1331, 1 990. 6. Steg, A., Leleu, C., Debre, B., Boccon-Gibod, L. and Sicard, D.: Systemic bacillus Calmette-Guerin infection, "BCGitis," in pa-
1500 7.
8.
9.
10. 11. 12.
FATAL MYCOBACTERIAL SEPSIS AFTER INSTILLATIO N O F BACILLUS CALMETTE- GUERIN
tients treated by intravesical bacillus Calmette-Guerin therapy for bladder cancer. Eur. Urol., 16: 161, 1989. Harris, H. W.: Pulmonary tuberculosis. In: Infectious Diseases: A Modern Treatise of Infections Processes, 4th ed. Edited by P. D. Hoeprich and M. C. Jordan. Philadelphia: J. B. Lippincott Co., chapt. 37, pp. 422-423, 1989. Des Prez, R. M. and Heim, C. R.: Mycobacterium tuberculosis. In: Principles and Practice of Infectious Diseases, 3rd ed. Edited by G. L. Mandell, R. G. Douglas, Jr. and J. E. Bennett. New York: Churchill Livingstone, part III, chapt. 229, pp. 1878-1884, 1990. Lage, J. M., Bauer, W. C., Kelley, D. R., Ratliff, T. L. and Catalona, W. J.: Histological parameters and pitfalls in the interpretation of bladder biopsies in bacillus Calmette-Guerin treatment of superficial bladder cancer. J. Urol., 13 5 : 916, 1986. Linn, R., Klimberg, I. W. and Wajsman, Z.: Persistent acid-fast bacilli following intravesical bacillus Calmette-Guerin. J. Urol., 141: 1 197, 1989. Armstrong, R. W.: Complications after intravesical instillation of bacillus Calmette-Guerin: rhabdomyolysis and metastatic infec tion. J. Urol., 1 4 5 : 1264, 1991. Aungst, C. W., Sokal, J. E . and Jager, B. V.: Complications of BCG
13. 14. 15. 16. 17. 18.
vaccination in neoplastic disease. Ann. Intern. Med., 82: 666, 1975. Mukamel, E., Vilkovsky, E., Hadar, H., Engelstein, D., Nussbaum, B. and Servadio, C.: The effect of intravesical bacillus Calmette Guerin therapy on the upper urinary tract. J. Urol., 146: 980, 1991. Biihle, A., Schuller, J., Knipper, A. and Hofstetter, A.: Bacillus Calmette-Guerin treatment and vesicorenal reflux. Eur. Urol., 17: 125, 1990. Gonzalez, J. A., Marco!, B. R. and Wolf, M. C.: Complications of intravesical bacillus Calmette-Guerin: a case report. J. Urol. , 1 48: 1892, 1992. Stanisic, T. H., Brewer, M. L. and Graham, A. R.: Intravesical bacillus Calmette-Guerin therapy and associated granulomatous renal masses. J. Urol., 135: 356, 1986. Modesto, A., Marty, L., Sue, J.-M., Kleinknecht, D., de Fremont, J.-F., Marsepoil, T. and Veyssier, P.: Renal complications of intravesical bacillus Calmette-Guerin therapy. Amer. J. Ne phrol., 1 1 : 501, 1991. Woods, J. M., 4th, Schellack, J., Stewart, M. T., Murray, D. R. and Schwartzman, S. W.: Mycotic abdominal aortic aneurysm in duced by immunotherapy with bacille Calmette-Guerin vaccine for malignancy. J. Vase. Surg., 7: 808, 1988.