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Sepsis and granulomatous hepatitis after bacillus Calmette-Guerin intravesical installation
Journal of Infection (2004) 48, 363–367
www.elsevierhealth.com/journals/jinf
Letters to the Editor Sepsis and granulomatous hepatitis after bacillus Calmette-Guerin intravesical installation Sir, Current data suggest that bacillus Calmette – Guerin (BCG) is the most effective agent available for the treatment of superficial bladder cancer, with few serious complications. However, BCG is a live strain of Mycobacterium bovis that, although attenuated, may exhibit some invasive properties. We describe a patient with a life threatening sepsis and hepatitis occurring after bladder instillation of BCG. Our case emphasizes some important points that should be taken into consideration: BCG is a live strain of mycobacteria and is capable of invasive behaviour; a diagnosis of BCG infection must be pursued in anyone who has had prior exposure to BCG; finally, empiric anti-tuberculous therapy should be considered while evaluation is underway. A 70-year-old previously healthy man was admitted to hospital with a 10-day history of fever (up to 40 8C), occurring soon after the fifth and traumatic BCG bladder instillation for transitional cell carcinoma. The results of a physical examination were unremarkable and a complete blood count was normal, except for the presence of leucopenia. Renal function was normal and liver function tests revealed the following results: aspartate aminostransferase (AST), (80 U/L, range 10 – 45); alanine aminotransferase (ALT), (129 U/L, range 5 – 55); alkaline phoshatase (ALP), (450 U/L, range 56 – 119); g-glutamyl transpeptidase (gGT), (385 U/L, range 3 – 65). Patient’s erythrocyte sedimentation rate (ESR) and C-reactive protein level were 95 mm/first hour and 107 mg/L (range, , 6), respectively. Routine blood and urine cultures did not yield any common pathogens and the results of serologic tests to assess virus and bacteria exposures were negative. Chest-X-ray, computerized tomographic scan of the abdomen and bronchoscopy were all normal. A urinary tract infection was suspected and a five day-course of ciprofloxacin was initiated. Despite antibiotic treatment, the patient’s clinical 0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
conditions progressively deteriorated and high fever persisted. Thus, a liver biopsy was performed. Histological examination showed several noncaseating epitheloid granulomas with Langhans’ giant cells (Fig. 1). Although acid-fast bacilli were not seen on Ziehl – Neelsen staining, isoniazid, rifampin, and ethambutol were prescribed, pending the results of blood and liver mycobacterial cultures. The patient gradually recovered, and fever subsided after 15 days of anti-tuberculous therapy. Liver abnormalities resolved during the following week. Six weeks later, a blood culture yielded Mycobacterium bovis, confirming the diagnosis of mycobacterial sepsis with liver involvement. Intravesical BCG is an effective treatment for superficial bladder cancer, with a success rate varying between 63 and 100%.1 Minor complications including hematuria, cystitis, fever (, 38.5 8C) and malaise are quite common, whereas major complications such as both local reactions (granulomatous prostatitis, epididymo-orchitis, ureteral obstruction, bladder contracture, renal abscess) and systemic reactions (fever . 39.5 8C, sepsis, granulomatous hepatitis and pneumonitis, arthralgias, cytopenia) may occasionally occur. In particular, sepsis and granulomatous hepatitis, are very uncommon, presented with an incidence of
Figure 1 Liver-biopsy specimen (hematoxylin and eosin, £ 100): well-formed, non-caseating granulomas with a Langhans’ giant cell (arrow).
364
0.4 – 0.7%, respectively, of patients undergoing BCG bladder instillation.2 – 4 BCG complications generally result from contiguous and hematogenous spread of intravesical mycobacteria through inflamed and/or disrupted urothelium most frequently caused by traumatic catheterisation, bladder perforation, or by an extensive tumour resection. In this setting, additional BCG intravesical instillations, with consequent exposure to a higher inoculum of viable micro-organisms, may increase the likelihood of subsequent severe reactions at distant sites. It is controversial how often these major systemic reactions are manifestations of invasive infection or a hypersensitivity reaction to BCG instillation.5 Indeed, in many series of reported cases, biopsy specimens of lung, liver, and bone marrow often reveal granulomas without acid-fast bacilli, and mycobacterial cultures of the same specimens and/or of blood often yield negative results. A recent analysis6 revealed that BCG infection could be stratified into early-and late-presenting disease; the early presentation (within 3 months after instillation) represents an immunocompetent host reaction to a relatively low-grade pathogen whereas the late presentation (after 1 year following the first instillation) represents a typical reactivation of mycobacterial disease after successful immunologic control of early dissemination. However, not all patients with early disease did fit this scheme. In our case, the growth of M. bovis from the blood culture confirmed the diagnosis of a disseminated infection. There has been no prospective study6 to evaluate the optimal treatment for BCG infection. In the cases of severe systemic reactions, some data support the administration of three anti-tuberculous drugs including isoniazid, rifampin and ethambutol lasting for at least 6 months. The use of pyrazinamide is not recommended because of its inactivity against M. bovis. The addition of corticosteroids during the first days of therapy may assist in a faster resolution of inflammatory complications.
References 1. Witjes JA, van der Meijden APM, Debruyne FMJ. Use of intravesical bacillus Calmette—Guerin in the treatment of superficial transitional cell carcinoma of the bladder: an overview. Urol Int 1990;45:129—136. 2. Lamm DL, Stogdill VD, Stogdill BJ, Crispen RC. Complications of bacillus Calmette—Guerin immunotherapy in 1,278 patients with bladder cancer. J Urol 1986;135:272—274. 3. Lamm DL. Complications of bacillus Calmette—Guerin immunotherapy. Urol Clin North Am 1992;19:565—572.
Letters to the Editor
4. Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treatment of complications of bacillus Calmette—Guerin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596—600. 5. DeHertogh D, Fierer E, Orell JA. Hypersensitivity reaction to bacillus Calmette—Guerin treated with plasmapheresis. Am J Med 1989;86:343—344. 6. Gonzales OY, Musher DM, Brar I, et al. Spectrum of bacillus Calmette—Guerin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis 2003;36:140—147.
Marco Trevenzolia, Anna Maria Cattelana,*, Filippo Marinob, Lolita Sasseta, Silvio Dona ` a, Francesco Meneghettia a Department of Infectious Diseases, General Hospital and University of Padua, Via Giustiniani 2, 35128 Padua, Italy b Unit of Pathology, General Hospital and University of Padua, Via Giustiniani 2, 35128 Padua, Italy E-mail address: [email protected] Accepted 23 January 2004 *Corresponding author. Tel.: þ39-49-8213741; fax: þ 39-498213768 doi:10.1016/j.jinf.2004.01.013
Performance of the OptiMAL dipstick test for management of severe and complicated malaria cases in a tertiary hospital, central India Sir, The need for better malaria diagnostics is clearly evident in tropical countries.1 The OptiMAL (Flow Inc., Portland, OR, USA) is a malaria antigen capture assay, which detects Plasmodium specific lactate dehydrogenase (pLDH), a marker protein for the intraerythrocytic forms of the malaria parasites.2 The OptiMAL test has recently been evaluated by us in detecting malaria infection in hospital and the field and found it very useful in detection of recrudescence and re-infection due to Plasmodium falciparum and P. vivax in an area where both species co-exist.3 This short report is about performance of OptiMAL test in management of serious and complicated cases of malaria admitted in a tertiary referral center, Government Medical College, Jabalpur. A malaria clinic of the Malaria Research Centre (Indian Council of Medical Research) is operational in the Medicine Department of the Government Medical College, Jabalpur where all fever cases and
www.elsevierhealth.com/journals/jinf
Letters to the Editor Sepsis and granulomatous hepatitis after bacillus Calmette-Guerin intravesical installation Sir, Current data suggest that bacillus Calmette – Guerin (BCG) is the most effective agent available for the treatment of superficial bladder cancer, with few serious complications. However, BCG is a live strain of Mycobacterium bovis that, although attenuated, may exhibit some invasive properties. We describe a patient with a life threatening sepsis and hepatitis occurring after bladder instillation of BCG. Our case emphasizes some important points that should be taken into consideration: BCG is a live strain of mycobacteria and is capable of invasive behaviour; a diagnosis of BCG infection must be pursued in anyone who has had prior exposure to BCG; finally, empiric anti-tuberculous therapy should be considered while evaluation is underway. A 70-year-old previously healthy man was admitted to hospital with a 10-day history of fever (up to 40 8C), occurring soon after the fifth and traumatic BCG bladder instillation for transitional cell carcinoma. The results of a physical examination were unremarkable and a complete blood count was normal, except for the presence of leucopenia. Renal function was normal and liver function tests revealed the following results: aspartate aminostransferase (AST), (80 U/L, range 10 – 45); alanine aminotransferase (ALT), (129 U/L, range 5 – 55); alkaline phoshatase (ALP), (450 U/L, range 56 – 119); g-glutamyl transpeptidase (gGT), (385 U/L, range 3 – 65). Patient’s erythrocyte sedimentation rate (ESR) and C-reactive protein level were 95 mm/first hour and 107 mg/L (range, , 6), respectively. Routine blood and urine cultures did not yield any common pathogens and the results of serologic tests to assess virus and bacteria exposures were negative. Chest-X-ray, computerized tomographic scan of the abdomen and bronchoscopy were all normal. A urinary tract infection was suspected and a five day-course of ciprofloxacin was initiated. Despite antibiotic treatment, the patient’s clinical 0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
conditions progressively deteriorated and high fever persisted. Thus, a liver biopsy was performed. Histological examination showed several noncaseating epitheloid granulomas with Langhans’ giant cells (Fig. 1). Although acid-fast bacilli were not seen on Ziehl – Neelsen staining, isoniazid, rifampin, and ethambutol were prescribed, pending the results of blood and liver mycobacterial cultures. The patient gradually recovered, and fever subsided after 15 days of anti-tuberculous therapy. Liver abnormalities resolved during the following week. Six weeks later, a blood culture yielded Mycobacterium bovis, confirming the diagnosis of mycobacterial sepsis with liver involvement. Intravesical BCG is an effective treatment for superficial bladder cancer, with a success rate varying between 63 and 100%.1 Minor complications including hematuria, cystitis, fever (, 38.5 8C) and malaise are quite common, whereas major complications such as both local reactions (granulomatous prostatitis, epididymo-orchitis, ureteral obstruction, bladder contracture, renal abscess) and systemic reactions (fever . 39.5 8C, sepsis, granulomatous hepatitis and pneumonitis, arthralgias, cytopenia) may occasionally occur. In particular, sepsis and granulomatous hepatitis, are very uncommon, presented with an incidence of
Figure 1 Liver-biopsy specimen (hematoxylin and eosin, £ 100): well-formed, non-caseating granulomas with a Langhans’ giant cell (arrow).
364
0.4 – 0.7%, respectively, of patients undergoing BCG bladder instillation.2 – 4 BCG complications generally result from contiguous and hematogenous spread of intravesical mycobacteria through inflamed and/or disrupted urothelium most frequently caused by traumatic catheterisation, bladder perforation, or by an extensive tumour resection. In this setting, additional BCG intravesical instillations, with consequent exposure to a higher inoculum of viable micro-organisms, may increase the likelihood of subsequent severe reactions at distant sites. It is controversial how often these major systemic reactions are manifestations of invasive infection or a hypersensitivity reaction to BCG instillation.5 Indeed, in many series of reported cases, biopsy specimens of lung, liver, and bone marrow often reveal granulomas without acid-fast bacilli, and mycobacterial cultures of the same specimens and/or of blood often yield negative results. A recent analysis6 revealed that BCG infection could be stratified into early-and late-presenting disease; the early presentation (within 3 months after instillation) represents an immunocompetent host reaction to a relatively low-grade pathogen whereas the late presentation (after 1 year following the first instillation) represents a typical reactivation of mycobacterial disease after successful immunologic control of early dissemination. However, not all patients with early disease did fit this scheme. In our case, the growth of M. bovis from the blood culture confirmed the diagnosis of a disseminated infection. There has been no prospective study6 to evaluate the optimal treatment for BCG infection. In the cases of severe systemic reactions, some data support the administration of three anti-tuberculous drugs including isoniazid, rifampin and ethambutol lasting for at least 6 months. The use of pyrazinamide is not recommended because of its inactivity against M. bovis. The addition of corticosteroids during the first days of therapy may assist in a faster resolution of inflammatory complications.
References 1. Witjes JA, van der Meijden APM, Debruyne FMJ. Use of intravesical bacillus Calmette—Guerin in the treatment of superficial transitional cell carcinoma of the bladder: an overview. Urol Int 1990;45:129—136. 2. Lamm DL, Stogdill VD, Stogdill BJ, Crispen RC. Complications of bacillus Calmette—Guerin immunotherapy in 1,278 patients with bladder cancer. J Urol 1986;135:272—274. 3. Lamm DL. Complications of bacillus Calmette—Guerin immunotherapy. Urol Clin North Am 1992;19:565—572.
Letters to the Editor
4. Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treatment of complications of bacillus Calmette—Guerin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596—600. 5. DeHertogh D, Fierer E, Orell JA. Hypersensitivity reaction to bacillus Calmette—Guerin treated with plasmapheresis. Am J Med 1989;86:343—344. 6. Gonzales OY, Musher DM, Brar I, et al. Spectrum of bacillus Calmette—Guerin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis 2003;36:140—147.
Marco Trevenzolia, Anna Maria Cattelana,*, Filippo Marinob, Lolita Sasseta, Silvio Dona ` a, Francesco Meneghettia a Department of Infectious Diseases, General Hospital and University of Padua, Via Giustiniani 2, 35128 Padua, Italy b Unit of Pathology, General Hospital and University of Padua, Via Giustiniani 2, 35128 Padua, Italy E-mail address: [email protected] Accepted 23 January 2004 *Corresponding author. Tel.: þ39-49-8213741; fax: þ 39-498213768 doi:10.1016/j.jinf.2004.01.013
Performance of the OptiMAL dipstick test for management of severe and complicated malaria cases in a tertiary hospital, central India Sir, The need for better malaria diagnostics is clearly evident in tropical countries.1 The OptiMAL (Flow Inc., Portland, OR, USA) is a malaria antigen capture assay, which detects Plasmodium specific lactate dehydrogenase (pLDH), a marker protein for the intraerythrocytic forms of the malaria parasites.2 The OptiMAL test has recently been evaluated by us in detecting malaria infection in hospital and the field and found it very useful in detection of recrudescence and re-infection due to Plasmodium falciparum and P. vivax in an area where both species co-exist.3 This short report is about performance of OptiMAL test in management of serious and complicated cases of malaria admitted in a tertiary referral center, Government Medical College, Jabalpur. A malaria clinic of the Malaria Research Centre (Indian Council of Medical Research) is operational in the Medicine Department of the Government Medical College, Jabalpur where all fever cases and