Multiple mycotic aneurysms due to Mycobacterium bovis after intravesical bacillus Calmette-Guérin therapy

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1 Multiple mycotic aneurysms due to Mycobacterium bovis after intravesical bacillus Calmette-Guérin therapy Raphael Coscas, MD, a * Jean-Benoît Arlet, MD, b * Denis Belhomme, MD, a Jean-Noël Fabiani, MD, a and Jacques Pouchot, MD, b Paris, France Mycotic aneurysms are exceptional complications after intravesical instillations of bacillus Calmette-Guérin (BCG) for bladder carcinoma. We report a patient who underwent an emergency operation for a ruptured carotid aneurysm 16 months after BCG therapy. Postoperative investigations discovered multiple other synchronous aneurysms. Culture of an abscess surrounding the right carotid artery identified Mycobacterium bovis var BCG. The patient improved clinically with antituberculous agents prescribed for 9 months but died from recurrence of bladder carcinoma 16 months later. A mycotic origin should be evoked when an aneurysm is discovered after BCG therapy. Microbiologic investigation of the artery wall is diagnostic. (J Vasc Surg 2009;50: ) Intravesical instillation of Calmette-Guérin bacillus (bacille bilié de Calmette et Guérin, BCG) is widely used for treatment of in situ bladder carcinoma and prevention of superficial bladder tumor recurrences. 1-3 Although this treatment is usually well-tolerated, serious complications such as disseminated granulomatous lesions in various organs have been reported. 4 Vascular complications are exceptional. CASE REPORT A 79-year-old man was referred to our hospital in October 2006 because of a painful mass in his neck. His medical history was significant for superficial bladder carcinoma operated on five times between 2001 and 2005 using transurethral resection. Adjuvant intravesical BCG-therapy (Immucyst, Sanofi Pasteur, Lyon, France) was administered every 6 months between February 2003 and June He did not take any other medication and had stopped smoking for 2 years. The patient complained of a pulsatile and enlarging mass on the anterior left side of his neck for a year. He denied any compression symptoms. He also complained of fatigue, poor appetite, and a 4-kg weight loss 18 months since the completion of the BCG therapy. The pain started 20 hours before the admission and was associated with a significant increase of the volume of the cervical mass. The physical examination showed he was cachectic (body mass index, 16 kg/m 2 ), afebrile (temperature, 37.2 C), and hemodynamically stable. A large mass was palpable at the anterolateral side of the neck. An ecchymosis extending from the neck to the left arm and the chest was noted. Results of a neurologic examination were normal. Laboratory tests noted anemia (hemoglobin, 8.5 g/dl) From the Departments of Cardiovascular Surgery a and Internal Medicine, b Faculté de Médecine Paris Descartes et Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou. *These authors contributed equally to this work. Competition of interest: none. Reprint requests: Dr Jean-Benoît Arlet, Service de Médecine Interne, Hôpital Européen Georges Pompidou, 20, rue Leblanc Paris Cedex 15 France ( jean-benoit.arlet@egp.aphp.fr) /$36.00 Copyright 2009 by the Society for Vascular Surgery. doi: /j.jvs and inflammatory response syndrome (white cell count 13,500/ L; C-reactive protein, 95 mg/l). Computed tomography (CT) scan of the head and neck revealed a 50-mm ruptured aneurysm at the left carotid artery bifurcation. A contralateral 26-mm aneurysmal mass was also demonstrated (Fig 1). Emergency surgery was performed. Left carotid artery bifurcation was approached through an incision along the anterior border of the sternocleidomastoid muscle. Surgical exploration confirmed the rupture, which appeared to be a pure defect of the arterial wall. The bifurcation was resected and a common-tointernal carotid artery bypass with polytetrafluoroethylene (PTFE) graft was completed. The external carotid artery was ligated. Pathologic examination confirmed the presence of an aneurysm of the left carotid bifurcation in an area of calcified and ulcerated atherosclerotic plaque. There was no granulomatous lesion. The patient s postoperative course was unremarkable. We operated on the contralateral side 10 days after admission and found no intraoperative evidence of carotid artery aneurysm. The carotid artery bifurcation was surrounded by an abscess resembling caseum. The carotid artery was moderately ectatic and inflammatory at this level. The abscess was drained and the bifurcation was resected. The common carotid artery was anastomosed end-to-end to the external carotid artery. The internal carotid artery was directly reimplanted in the external carotid artery without any graft interposition. The patient s postoperative course was uneventful. Pathologic examination showed necrotizing granulomatous inflammation of the arterial wall and moderate calcifications of an atherosclerotic plaque. Bacteriologic examination of the abscess sample showed a rare acid-fast organism. Polymerase chain reaction (PCR) was positive for Mycobacterium tuberculosis complex, and culture in Lowenstein-Jensen medium identified M bovis var. BCG. Results of multiple sputum and urine cultures were negative for acid-fast organisms. Results of serology for HIV-1 and HIV-2 were negative. Echocardiography did not find any valvular vegetation or a patent foramen ovale. A postoperative CT scan found four other saccular aneurysms located on the descending thoracic aorta, the infrarenal aorta, the left external iliac, and the left posterior tibial arteries (Fig 2). All of these aneurysms had a diameter of 10 mm and were not consid- 1185

2 1186 Coscas et al JOURNAL OF VASCULAR SURGERY November 2009 Fig 1. Computed tomography scan of the head and neck showed (A, B) a 50-mm ruptured aneurysm of the left carotid bifurcation (white arrow and [B], black arrows), and (C) a 26-mm mass of the right carotid bifurcation (white arrow). Fig 2. A postoperative computed tomographic scan revealed multiple saccular aneurysms located of (A) the left iliac artery, (B) the abdominal aorta, and (C and D) the thoracic aorta. ered for surgical treatment. Magnetic resonance angiography did not reveal any intracranial aneurysm. The patient was discharged 25 days after admission with oral antituberculous medications, including isoniazid, ethambutol and rifampicin for 2 months, followed by isoniazid and rifampicin for 7 additional months. He improved gradually, but a recurrence of bladder carcinoma was diagnosed at the 6- month follow-up, mandating cystectomy. The patient died of bladder cancer progression 16 months after initiation of the antituberculous therapy. The four remaining aneurysms were stable on the final follow-up CT scan performed 1 month before the patient died. DISCUSSION BCG is a strain of M bovis that has been rendered avirulent after being cultured on a beef bile medium for

3 JOURNAL OF VASCULAR SURGERY Volume 50, Number 5 Coscas et al 1187 Table. Reported cases of mycotic aneurysms due to Mycobacterium bovis after bacillus Calmette-Guérin therapy a First author Age Sex Time from BCG-therapy (mon) Location Woods 6 62 F 17 Infrarenal aorta Bornet 7 74 M 26 Left femoral artery Right femoral artery Deresiewicz 8 67 M 14 Infrarenal aorta Iliac artery Izes 9 69 M 36 Aortic arch Wolf M 24 Infrarenal aorta Hellinger M 25 Infrarenal aorta Rozenblit M 69 Infrarenal aorta Damm M 4 Infrarenal aorta LaBerge M 8 Infrarenal aorta Seelig M 30 Infrarenal aorta Seelig M 53 Infrarenal aorta Popliteal pseudoaneurysm Farber M 12 Femoral artery Geldmacher M 24 Carotid artery Kamphuis M 12 Infrarenal aorta Suprarenal aorta Wada M 32 Abdominal aorta Femoral artery Witjes M 4 Popliteal artery Dahl M 18 Infrarenal aorta Harding M 24 Infrarenal aorta Safdar M 11 Infrarenal aorta Costiniuk M 24 Infrarenal aorta Femoral artery Present case 79 M 18 Infrarenal aorta Thoracic aorta Iliac artery Posterior tibial artery Left carotid artery Right carotid artery Total 72 (58-80) b 20 M 23 (4-69) b 14 unique aneurysms 1 F 7 multiple aneurysms EA, Extra-anatomic; F, female; IS, in situ; M, male; NS, not specified. a Including the present report, 31 aneurysms in 21 patients were identified in the literature since b Mean (range). c Mean follow-up of patients who were alive 1 month after the initial presentation. many years. It has been used as a vaccine against human tuberculosis since the 1920s and as immunotherapy for cancer since the mid-1970s. Intravesical administration of BCG is used as an effective treatment for in situ bladder carcinoma, recurrent stage Ta disease, and immunoprophylaxis after endoscopic resection of stage Ta or T1 disease. 1,2 Immucyst is the only available formulation in France, but five other strains are available commercially (Tice, Connaught, RIVM, Tokyo, Danish), with no difference in preventing tumor progression. 3 Treatment protocols include an induction phase with 6 to 12 weekly intravesical instillations, followed by more spaced out maintenance instillations for 3 to 9 months. 1-5 The mechanisms through which BCG acts are unclear, but induction of a local granulomatous inflammation is thought to have an effect in killing tumor cells. 4 Intravesical BCG instillations are generally considered safe. According to Lamm et al, 5 the most common complications among 2602 patients were fever (2.9%), hematuria (1%), infectious granulomatous complications such as prostatitis, and pneumonia, hepatitis, and life-threatening BCG sepsis ( 1%). No arterial involvement was reported in their study. To date, 21 patients (including our patient) were found to have 31 aneurysms after BCG therapy (Table) Mean age at diagnosis was 72 years (range, years), and aneurysms were diagnosed a mean of 23 months (range, 4-69 months) after BCG therapy. Episodes of fever or fatigue during or immediately after BCG instillations were reported by 11 patients (52%), but were absent in our patient. The most frequent clinical symptoms at presentation were abdominal or back pain in 12 (57%), general malaise in 11 (52%), fever in 8 (38%), and pulsatile or painful mass in 4 (19%). The abdominal aorta was involved in 16 patients (76%), but aneurysms of the aortic arch, 9 the femoral arteries, 7,16,19,24 the popliteal artery, 15,20 and the carotid artery 17 were also reported. Similar to our patient, 11 patients (52%) presented with rupture, with histologic finding of arterial wall necrosis in most. Several patients were immunocompromised at the time of diagnosis because of corticosteroid therapy 8,9,11,15 or chemotherapy. 6

4 1188 Coscas et al JOURNAL OF VASCULAR SURGERY November 2009 Table. Continued. Type of surgery Antibiotic therapy Duration (mon) Follow-up Status at last follow-up IS prosthesis NS 11 mon Alive, healthy IS prosthesis mon Alive, healthy IS vein EA prosthesis... Several wk Died disseminated Mycobacterium infection... 9 d Died, palliative care IS prosthesis mon Alive, aortoenteric fistula at 20 mon IS prosthesis mon Alive, healthy Stent graft NS 15 mon Died, myocardial infarction IS prosthesis NS 8 mon Alive, healthy EA prosthesis NS NS NS... IS prosthesis mon Alive, healthy IS prosthesis mon Alive, healthy Popliteal prosthesis removal IS vein NS 6 mon Alive, healthy IS vein NS NS IS prosthesis... 1 d Died, post-op shock IS prosthesis mon Alive, healthy IS prosthesis NS 41 mon Alive, healthy IS prosthesis 9 36 mon Alive, healthy IS prosthesis mon Alive, healthy EA prosthesis 12 3 mon Alive, healthy IS prosthesis 12 9 mon Alive, aseptic pseudoaneurysms IS vein 9 16 mon Died, cancer progression IS prosthesis Resection-anastomosis... 15/ mon 26 (3-128) c mon... In our patient, advanced age and poor general status may have participated in the dissemination of the infection. Assuming the routes of infection are similar to M tuberculosis, three different mechanisms could explain an arterial infection by M bovis 25 : 1. direct intimal colonization during an hematogenous dissemination, especially in the setting of an altered arterial wall by atherosclerosis; 2. metastatic implantation of the bacteria through adventitial vasa-vasorum, or 3. local vascular extension of an infected site such as contiguous lymphadenitis. The presence in our patient of multiple aneurysms without any suspected lymph node involvement supports the hypothesis of hematogenous dissemination. The smoking history, the occurrence of these aneurysms in typical atherosclerotic localizations, and the presence of left carotid artery atherosclerosis at the first surgical procedure suggest a direct intimal invasion. Conversely, an abscess surrounded the right carotid artery, which could favor the explanation of a metastatic implantation through the vasavasorum. Definitive diagnosis of M bovis var. BCG infection is obtained by culture, which remains the gold standard. It was positive in all but one reported case. 8 Other diagnostic tests with lower specificity were also reported and include direct acid-fast bacilli detection, 6-12,14,15,17,18,20-24 evidence of typical caseating granulomatous lesions, 6,7,9,13,17-23 and PCR 10,18 from various tissue samples. The ideal therapeutic management remains controversial. Although 14 patients (71%) were treated with a combination of antituberculous medications and surgical therapy, several were treated with surgery alone, 8,10,18,19 and one popliteal aneurysm completely resolved after antituberculous therapy alone. 20 No recurrences were noted during follow-up of patients who received appropriate antibiotic therapy, regardless of the surgical repair. Conversely, four of the five patients who did not receive an antituberculous therapy

5 JOURNAL OF VASCULAR SURGERY Volume 50, Number 5 Coscas et al 1189 experienced infectious recurrences or early death. 8-10,18 Therefore, therapy with a combination of at least three antibiotic agents is recommended in all patients for extended durations of 9 to 12 months. M bovis is naturally resistant to pyrazinamide, which should not be used. During surgical repair, resection of all infected arterial tissues should be considered for large aneurysms. In the setting of an infected operative field, revascularization with in situ biologic conduits or extra-anatomic bypasses remains a logical option. Autologous vein grafts 7,17,24 and extra-anatomic 14,23 bypasses were successfully performed. Although never reported, autologous arterial grafts or cryopreserved allografts could be used as alternative conduits. Our review highlights that several in situ prosthetic conduits 6,7,11,13,15,21,22,24 and one stent graft 8 were used without any infectious complication when combined with antituberculous medications. In our patient, we used an in situ prosthetic graft for the left carotid artery because the aneurysm etiology was unknown at the time of the repair. No infectious recurrence was noted during the 16-month follow-up. Similar results were reported in the treatment of mycotic aneurysms due to M tuberculosis. 26 These findings emphasize the need for an experimental evaluation of the vulnerability of vascular grafts to mycobacterial infection. Medical management alone could be an option for some patients. Witjes et al 20 reported the complete regression of a popliteal aneurysm after 4 months of antibiotic therapy; however, the aneurysm diameter was not stated. Four small aneurysms (diameter 10 mm) in our patient were not resected and remained stable, but the follow-up duration was limited by his death at 16 months. Although we cannot provide a clear therapeutic algorithm due to the limited number of cases, an antibiotic therapy alone could be an alternative to resection for small asymptomatic aneurysms. CONCLUSIONS Mycotic aneurysm due to M bovis is an exceptional complication of BCG therapy. This is a life-threatening complication because rupture is frequent, occurring in more than half of reported patients and requiring emergency surgical treatment. Small asymptomatic aneurysms could be managed with antibiotic therapy alone, whereas a combination of antituberculous therapy and surgical repair is the treatment of choice for larger aneurysms. 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