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October - December 2007: 
Volume 20, Issue 4

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Granulomatous pneumonitis after intavesical instillation of BCG in a patient with bladder carcinoma
Abstract
SUMMARY. A rare case is presented of granulomatous pneumonitis following intravesical instillation of Bacillus Calmette-Guerin (BCG) for the treatment of superficial urothelial carcinoma. The patient, a 59 year-old man, was admitted to hospital because of malaise, fever (39o C), dyspneoa (III/IV) and respiratory failure. He had a history of urinary bladder carcinoma treated by transurethral resection, followed by repeated instillations of BCG, a live attenuated strain of Mycobacterium Bovis, every 4 months, as immunotherapy. After the 4th instillation the patient progressively developed the symptoms that led to his admission. Physical examination revealed inspiratory crackles in both lung fields. Radiological examination with X-ray and HRCT showed bilateral patchy alveolar infiltrations, a ‘ground glass’ appearance of the lungs and multiple pulmonary nodules in the middle and lower lung zones. Laboratory examination excluded other causes of granulomatous diseases. The administration of antituberculous treatment and corticosteroids resulted in rapid clinical and radiological improvement. Pneumon 2007; 20(4):401–405
Full text
INTRODUCTION

Bladder cancer is the second most common malignancy of the uninary tract. WHO reports 250,000 new cases of bladder cancer and 120,000 deaths from this cause annually1,3. There are two types of bladder cancer: 1) superficial, localized to the mucosa, and 2) invasive, involving the muscular wall, with possible extension outside the bladder wall. Intravesical instillations of live attenuated tuberculous mycobacteria, Bacillus Calmette-Guerin (BCG) have become a mainstay of adjunctive therapy for the treatment of the superficial type of bladder cancer after the transurethral resection of the tumour, and for the prevention of local recurrences. This form of treatment may have local, regional and systemic complications. Systemic complications are rare but they are serious, and one of them is granulomatous pneumonitis, with an incidence of less than 0.7%1,2,4,7,8. The case is described of granulomatous pneumonitis in a patient with bladder cancer following immunotherapy with intravesical instillation of BCG.

CASE REPORT

A 59 year-old man, who was a former smoker (25py, ceased 15 years earlier) presented with a 15-day history of malaise, fever (39 °C) and dyspnoea (III/IV). His past medical history included a right inguinal hernia, and superficial bladder cancer treated by transurethral resection one year earlier, followed by 4 intravesical instillations of BCG. After the last instillation, fifteen days prior to admission, the patient developed the symptoms described above for which he received outpatient treatment with cefuroxime 500mg x 2 per os without improvement. The clinical findings on admission included: Blood pressure 80/60mm Hg, T 39°C, pulse 111/min, with sinus tachycardia on ECG. On auscultation the respiratory sounds were diminished and bilateral fine inspiratory crackles were detected. Examination of the other systems was normal. Tuberculin Mantoux skin test was 0.0 mm. Arterial blood analysis showed severe hypoxaemia with respiratory alkalosis (FiO2 0.21, pH 7.56, pO2 42 mmHg, pCO2 29 mmHg, HCO3 26 mmol). Haematological and biochemical examination was normal, with the exception of: ESR 54 mm/1h, urea 54 mg/dl (normal values 8-50), creatinine 1.4 mg/dl (normal 0.7-1.3), ALP= 212 U/l (53-128), LDH= 240 U/l (100-190), Na 131mmol/l, CRP= 23.88 mg/dl (<0.5). The cause of the mild renal failure was attributed to water deficit due to fever, the high levels of ALP and LDH were attributed to the underlying malignancy, and the mild hyponatraemia to concomitant pulmonary disease. Chest X-ray showed a combination of diffuse alveolar opacities and nodules predominantly in the middle and lower lung zones, especially in the right lung (Figure 1 a, b). High resolution computed tomography (HRCT) showed a bilateral ‘ground glass’ appearance, patchy alveolar infiltrations in the middle and lower lung zones and irregular alveolar opacities especially in the posterior zones of the right lung, suggestive of masses, and multiple pulmonary nodules (Figure 2 a, b, c, d, e). No hepatic or splenic granulomas were detected on ECHO examination. Repeated sputum and bronchoscopic specimens cultured for common pathogens and fungi, stained by Ziehl-Neelsen and cultured for Mycobacterium tuberculosis were negative. Gastric fluid examination for M. tuberculosis also was negative. PCR for mycobacteria (M. Tuberculosis, M. bovis) and fungi was negative. Immunofluorecence for PCP and serological tests for viruses, Ricketsiae and Chlamydia sp. were negative. Immunological testing (ANA, anti-DNA, LE-cells, c-ANCA, p-ANCA) produced negative results.


Figure 1 a, b. Postero-anterior and lateral chest X-ray showing bilateral alveolar infiltrations and multiple

pulmonary nodules localized specifically in the middle and lower zones, predominantly in the right lung.


Figure 2 a, b, c, d, e. High resolution
computed tomography showing multiple
pulmonary nodules surrounded by diffuse
alveolar infiltrations, especially in the middle
and lower lung zones, with ‘mass-like’
formation in the posterior segments, and
patchy ‘ground glass’ appearance.

At the time of his admission the patient was started on oxygen therapy (MV 50%), intravenous kefepime (1gr x 2) and intravenous clarithromycin (500 mg x 2). Because of lack of improvement of his clinical status and subsequent suspicion of systemic complications of the intravesical instillation of BCG, antituberculous treatment was administered (isoniazide 300 mg, rifampicine 600 mg, ethambutol 1500 mg and levofloxacin 500 mg x 2 daily). Due to severe respiratory failure and progressive deterioration of the radiography findings (Figure 3 a, b) the patient was admitted to the intensive care unit (ICU) where, in parallel with mechanical ventilation, he received intravenous administration of corticosteroids (prednisone 75 mg). Progressive improvement was observed and after 5 days of hospitalization in the ICU the patient was transferred to the pulmonary department where he remained for a further 15 days until his discharge. He continued to take isoniazide, rifampicin and prednisolone 40mg daily per os for 9 months, while the prednisolone was tapered off progressively two months after his discharge. He had monthly follow-up examination as an ambulatory patient for one year, during which period he remained free of symptoms and radiographic findings (Figure 4 a, b).

Figures 3 a, b. Deterioration of chest X-ray before ICU admission.

Figures 4 a, b. Normal chest X- ray at two-months follow-up.

DISCUSSION

Bladder cancer is the second most frequent maligamines, anilines). Other risk factors include the use of synthetic carbohydrates, chronic use of analgesics, pelvic radiotherapy, excessive consumption of coffee or tea, chronic inflammation (cystitis, indwelling catheters and cyclophosphamide therapy1,3,5.

Superficial bladder cancer represents 75% of all bladder malignancies, while 20% are the invasive type and 5% are metastatic on diagnosis. Invasive bladder carcinoma needs direct and radical therapy. Surgical treatment in the early stages gives better results. Owing to the possibility of recurrence in more than 80% of cases of superficial carcinoma, the target of treatment is the resection of the tumour and the avoidance of recurrence of the disease and its transition into invasive carcinoma. For this reason protocols were developed for intravesical chemotherapy after tumour resection, but then the introduction of intravesical BCG radically changed the therapeutic approach to superficial bladder cancer. Nowadays, following tumour resection, the intravesical instillation of BCG, which contains live attenuated bacilli of M. bovis, is considered to be an effective and safe form of treatment5-8. The use of BCG immunotherapy was described for the first time in 1929, following the observation that a group of patients with tuberculosis had a lower percentage of malignancies compared with the rest population. In 1976 BCG was administered for first time intravesically for the treatment of superficial bladder cancer and its effectiveness is based on studies showing that >70% of patients with transitional bladder carcinoma presented a complete response4,6,7. BCG instillations constitute a mode of immunotherapy, a special type of treatment in which these agents are used for immune stimulation. Their mechanism of action in bladder cancer is unknown but the BCG instillation probably acts as a non-specific stimulant to the immune system, inducing the formation of granulomatous inflammation. The first instillation should be performed at least 2-3 weeks after tumour resection. Exclusion criteria are immunocompromised patients those with active tuberculosis, and treatment must be delayed in patients with fever, bleeding or infections for which the administration of antibiotics is necessary.

This form of treatment is well tolerated, although in many cases complications are observed at the beginning of treatment or during the course of sessions. In the patient described, the complication became apparent after the 4th instillation. The complications are classified as local, regional and systemic1,8. Systemic complications, although rare are the most severe, and the most frequent of these is fever, but temperatures of >39oC are rare and are observed in only 2.9% of patients. Other rare complications are granulomatous pneumonitis (0.7%), granulomatous hepatitis (0.7%), the formation of mycotic aneurysms, reactive arthritis (0.5%), bone infections, skin rash, myelotoxic action, sepsis and death6-8.

Regarding the mechanism of action by which the instillation of BCG induces the complications there is disagreement about whether it represents a hypersensitivity reaction or an actual infection. The hypersensitivity reaction theory was based on the presence of granulomas and the absence of pathogens in the affected tissues. The response to corticosteroids in combination with anti-tuberculous drugs confirms the role of hypersensitivity7,8, although, in some cases of granulomatous pneumonitis pathogens were isolated and cultured5,7,8. The results of several studies are contradictory. M. bovis has been identified by PCR in some cases of granulomatous pneumonitis, but in other cases the results of PCR were negative, as in the case described here. It is evident that both mechanisms may be involved in the pathogenesis of complications and must be taken into consideration when planning treatment.

After damage to the urothelial cells, M. bovis easily moves into local lymphatic and blood vessels and migrates to other tissues2,3.

In the case of granulomatous pneumonitis a characteristic miliary pattern or nodules with local inflammatory infiltrations are observed on chest X-ray and CT11. The symptoms are fever, malaise, fatigue and dyspnoea, followed quickly by severe respiratory failure, as in the patient reported, who showed progressive deterioration of his respiratory function, possibly because of the absence of suspicion of tuberculous granulomatous pneumonitis on his admission (he was initially treated for severe pneumonia with broad spectrum antibiotics)10. Comprehensive microbiological testing (sputum cultures, Ziehl-Neelsen stain, PCR) should be performed, although in the majority of patients the results will be negative. Patients with granulomatous pneumonitis must be hospitalized and receive appropriate treatment, which includes antituberculous drugs with or without corticosteroids, and the BCG instillations must be stopped definitively4,6,7,9.

M. Bovis is sensitive to most antituberculous drugs with the exception of pyrazinamide. The recommended regime includes isoniazide 300 mg/day per os and rifampicin 600mg/day per os for 3 to 6 months6-9. The early use of corticosteroids is recommended at a dose of 40mg/ day per os7,8. The delay in administration of corticosteroids in the reported patient is believed to have been the determining factor in his deterioration. The administration of corticosteroids leads to rapid improvement of symptoms and to inhibition of granuloma formation, and may in some cases prevent sepsis.

Some studies support the prophylactic use of corticosteroids during instillations of BCG, although no difference in the prevalence of complications has been observed after their prophylactic use1,3,5,7.

REFERENCES

1. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics 2002. CA Cancer J Clin 2002; 52:23- 47.
2. Βohle A, Jochram D. Intravesical Immunotherapy with BCG, facts, figures and results. Urban & Fischer Verlag, Munchen, Jena 1988/2000.
3. Messing E. Urothilial tumors of the urinary tract. Charter 76, Campells Urology 3rd Edicion 1997; 2.327-2.390.
4. Elkabani M, Greene JN, Vincent AL, et al. Disseminated Mycobacterium Bovis after intravesicular BCG treatments for bladder cancer. Cancer Control 2000; 24:1139.
5. McParland C, Cotton DJ, Gowda KS, et al. Miliary Mycobacterium bovis induced by intravesical BCG immunotherapy. Am Rev Respir Dis 1992; 146:1330.
6. Lamm DL. Complications of BCG imunnotherapy. Urol Clin North Am 1992; 19:565-572.
7. Kesten S, Title L, Mullen B, et al. Pulmonary Disease following intravesical BCG treatment. Thorax 1990; 45:709-710.
8. Lantorno R, Nicolai M, Storto ML, et al. Miliary tuberculosis of the lung in a patient treated with BCG for superficial bladder cancer. J Urol 1998; 159:1639-1640.
9. Reparaz J, Uriz J, Castiello J, Sola J. Miliary tuberculosis after intravesical BCG administration. Enferm Infecc Microbiol Clin 1993; 11:570. Spanish.
10. Rival G, Garot D, Mercier E, et al. Acute respiratory failure and septic shock induced by Mycobacterium bovis. A rare side effect of intravesical BCG. Therapy J. Presse Med 2006; 35: 980.
11. Mignon F, Chevriere A, Mesurolle B, et al. Miliary induced by intravesical BCG immunotherapy for carcinoma of the bladder: CT findings. J. Radiol. 2002; 83:368.

References