Clinical Meetings at RH Year 2001

2001 - TB or Not TB, that is the question

Dr WS Leung, Dr CM Chu; United Christian Hospital

Case Report
The patient was a 66-year-old gentleman. He was an ex-chronic smoker and non-drinker. He was admitted to the medical ward on 28 December 1999 because of fever, shortness of breath and mild ankle edema.

Significant past medical history included schizophrenia in remission, hypertension, hyperlipidemia, and gout. He also has ischaemic heart disease and percutaneous transluminal coronary angioplasty with stenting to the left anterior descending artery was done in April 1997. He belonged to the New York Heart Association Class II. He had transitional cell carcinoma of the left renal pelvis, with left nephrectomy done in January 1998. The histology was papillary type (WHO grade II) and resection margin was clear. Unfortunately, the transitional cell carcinoma recurred in the urinary bladder and he received transurethral resection of bladder tumor (TURBT) in September 1998. Later on he received Bacillus Calmette-Guerin (BCG) immunotherapy after the operation. Otherwise, he had no history of tuberculosis or recent travel.

On admission, the blood pressure was 120/50 mm Hg, the pulse was 80/minute, the temperature was 36°C, and the oxygen saturation was 95% on 24% oxygen. Other examination only showed mild heart failure. However he soon ran a fever after admission. CXR showed mild heart failure and ECG showed no acute ischaemic changes. Initial blood test results were as follows (Table 1). The problem was sepsis, with liver and renal function impairment.



Clinical Course
For the liver derangement, hepatitis markers for Band C were negative. Ultrasounography of the liver showed no focal lesion, except a small gall stone. Enteroscopic retrograde cholangio-pancreatography (ERCP) was also normal. For the impaired renal function, investigations including urine microscopy, culture, and ultrasounography were all normal.

His condition deteriorated further. He had persistent fever for more than 2 weeks and significant weight loss from 81kg to 69kg over 1 month. The liver and renal function test deteriorated further. Blood, urine culture were both negative. Sputum grew some Acinetobacter, but he did not respond to the antibiotic given. Workup for pyrexia of unknown origin, including Widal test, Weil-Felix test, malaria screen, echocardiography were all negative. Bone marrow was performed in view of persistent fever and worsening pancytopenia. It showed normal trilineage haematopoiesis and noncaseating epitheloid granulomas, but Ziel Nielson (ZN) stain showed no acid-fast bacilli (AFB).

At this juncture, the respiratory team was consulted for the possibility of tuberculosis and the appropriate anti-tuberculosis regimen in view of the deranged liver and renal function. We reviewed the history again and found a very important piece of information. This patient was under the care of our urologist for carcinoma of bladder. He received review cystoscopy in June 1999 and it showed an erythematous patch over the bladder wall, and biopsy was granulomatous inflammation with acid fast bacilli present. It was a common finding after intravesical BCG therapy and required no treatment. However, on 25 December 1999, ie 3 days prior to admission of this episode, he had a traumatic catherization of the bladder and intra-vesical BCG therapy was still given. We suspected that disseminated BCG infection might account for the illness, in view of the temporal relationship of the illness and the BCG therapy. Repeat bone marrow examination and liver biopsy were suggested, but patient only agreed for the liver biopsy. The liver biopsy showed noncaseating granulomas consisting of epitheloid histiocytes; occasional multinucleated giant cells and ZN stain showed positive AFB (Figure 1).



Diagnosis
Disseminated BCG infection after BCG immunotherapy for the carcinoma of bladder

Clinical Course after Treatment
Specific treatment including isoniazid 300 mg daily, rifampicin 600mg daily, and ethambutol Ig every two day were started on 10 February 2000. He had prompt improvement in the general well being and all the biochemical parameters (Figure 2 and 3). He was later transferred to chest hospital for continuation of treatment.





Review of Disseminated Bacillus Calmette-Guerin (BCG) Infection after Immunotherapy of the Bladder Carcinoma
What is BCG?
BCG is an attenuated strain of living bovine tubercle bacillus, Mycobacterium bovis. Immunotherpeutic BCG (Immuncyst) used in carcinoma of bladder is made from a Connaught strain of BCG. The bacilli are freeze-dried and are viable upon reconstitution. Each vial contains no less than 60 million units of BCG, which is 720 times of the dose for routine BCG vaccination.

Role of BCG in the Treatment of Carcinoma of Bladder
BCG immunotherpy promotes a local acute inflammatory and subacute granulomatous reaction with histiocytic and leukocytic infiltration in the urothelium and lamina propria. It results in elimination or reduction of superficial cancerous lesion. It is indicated for treatment and prophylaxis of primary or recurrent carcinoma-in-situ of bladder carcinoma. It is also used as prophylaxis following TURBT of primary or recurrent superficial papillary

Adverse Effects
Lamm and colleagues have determined the frequency of BCG reactions after intra-vesical BCG therapy in 2 studies [1,2], the second of which involved 2606 patients. The reactions may be local, involving the urinary tract or adjacent structures, or systemic. It may be mild or severe.

Mild cystitis develops in most patients after the intravesical BCG, and hematuria develops in a bout a third of the patients. The symptoms usually start within 2 to 4 hours after instillation and abate within 48 hours. Severe local effects include, in order of decreasing frequency, granulomatous prostatis (in 0.9% of patients), epididymoorchitis, urethral obstruction, bladder contracture, and renal abscess (0.1%).

Mild transient fever and malaise develop in most patients. The most common symptom of severe systemic disease is a high temperature (>39C), which occurs in 3% of patients. The fever generally resolves in one to two days, but very high or persistently high fever may signal active BCG infection or a severe immune reaction. In such cases, it is difficult to tell which patients will subsequently have more serious complications. It is therefore recommended that all patient with a temperature higher than 38.5°C for 12 to 24 hours be treated with isoniazid for three months and that BCG treatments be discontinued until the symptoms have disappeared [2]

Serious complications of disseminated BCG infection occur in less than 1% of patients. Lamn reported granulomatous hepatitis and pneumonitis in 0.7% of patients and full-blown sepsis in 0.4%; seven deaths from sepsis after the intravesical use ofBCG. The mortality rate is about 1 in 12,500 [2].

Talbot et al proposed a working definition for disseminated BCG infection [3]. Cases were defined as definite disseminated BCG disease when all three of the following conditions were met.

1. BCG cultured and identified by biochemical methods at least.
2. Dissemination evidenced by either A or B.
a. A positive blood or bone marrow culture
b. Evidence of infection at two or more anatomic sites beyond the region of vaccination or instillation. Evidence of infection includes a positive culture or histopathologic demonstration of acid-fast bacilli. Examples of acceptable sites include the following: lymph node or nodes beyond the ipsilateral axillary lymph nodes; one or more cutaneous abscessed beyond the region of vaccination; osteomyelitis at one or more sites; brain or CSF; lung biopsy specimen, sputum, pleura and/or pleural fluid, or gastric aspirate; liver; spleen; intestine and/or stool; and kidney and/or urine. Multiple isolates from the same organ system are counted only once. For example, infection of multiple distant lymph nodes constitutes one site. Isolation of BCG from both sputum and pleural fluid constitutes one site.

3. A systemic syndrome compatible with mycobacterial disease. Typical manifestations include fever, weight loss, anemia, and death.

Pathogenesis
When systemic reactions develop, the role of BCG can be difficult to establish because mycobacteria usually cannot be demonstrated on smears, cultures of the lesion, blood or bone marrow. Even attempts to detect organism by DNA probe have sometimes failed in cases of granulomatous hepatitis, sepsis, and local granulomatous reactions in the urinary tract. The paucity of organism may reflect a high level of immunity [4]. Disseminated BCG infection usually occurs after traumatic catheterization. Treatment
BCG is susceptible in vitro to all antituberculosis drugs except pyrazinamide. In animals, the combination of isoniazid and rifampicin appears to be a satisfactory antituberculosis agent, although many physicians would administer three or four agents, including ethambutol [5]. Amoxicillin-clavulanic acid, most aminoglycosides, tetracyclines, sulfamethoxazole, and norfloxacin are active in vitro. Corticosteroid, eg prednisolone 0.5 to I mg/kg/day is used in severe sepsis syndrome or if the initial response to anti-tuberculosis treatment is not satisfactory [5].

References

1. Lamm DL, Stogdill VD, Stogdill BJ, et al. Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J Urol1986; 135:272-274.
2. Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial ladder cancer, J Urol1992; 147:596-600.
3. Talbot EA, Perkins MD, Silva SFM, et al. Disseminated Bacille Calmette-Guerin disease after vaccination: case report and review. CID1997; 24: 1139-1146.
4. Lamm DL. Complications of bacillus Calmette-Guerin immunotherapy. Ural Clin North Am 1992; 19:565-572.
5. DeHaven 11, Traynellis C, Riggs DR, et al. Antibiotic and steroid therapy of massive systemic bacillus Calmette-Guerin toxicity. J Urol1992; 147:738-742.