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Aortic BCGitis should be considered in patients with a history of BCG therapy presenting with fever, fatigue, pain and aortic aneurysm.
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Other synchronous localizations should be searched for on PET/CT.
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Mycobacteria research should be mandatory in surgical samples.
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Histology showing granulomas is often crucial for a definitive diagnosis.
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Management often implies surgical treatment and antituberculous therapy for at least a 9-month course.
Introduction
Intravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for in situ bladder carcinomas; however, extravesical BCG infection may occur in remote organs in patients with underlying primary immunodeficiency and is a potentially serious complication in 3–5% of cases. It includes granulomatous pneumonia, hepatitis as well as specific dermatological, ophthalmic, and haematopoietic manifestations. Diagnosis is difficult and often based on high clinical suspicion as in many cases Mycobacterium bovis is not isolated. This report presents a rare case of BCGaortitis treated in a tertiary care centre.
Report
A 74 year old man, with a history of bladder cancer treated with BCG therapy over a year ago, presented with malaise, abdominal pain, anorexia, and significant weight loss for several months associated with acute on chronic renal failure and a tender aneurysm. He was diagnosed with hepatic BCGitis and pararenal BCGaortitis. He was considered too high risk for open surgery after a multidisciplinary team meeting and was treated with a four vessel physician modified endograft (PMEG) and antituberculous therapy. At seven month follow up, he was clinically well and control computed tomography showed a patent endograft with complete exclusion of the aortic aneurysm.
Discussion
Infectious BCG complications after intravesical BCG administration for in situ bladder carcinomas can lead to severe early and late complications. In the present case, the patient presented with both liver and aortic BCG infection. The lack of positive microbiological data should not discourage clinicians from considering BCG infection even if several months have passed since the last BCG instillation.
Aortitis may present as fever, fatigue, and malaise caused by systemic inflammation, or more specific symptoms depending on location. Left undiagnosed, aortitis can lead to aneurysm formation, rupture, and ultimately death. It can be caused by septic emboli, contiguous spread from adjacent structures, haematogenous dissemination, or surgical intervention. Infective native aortic aneurysms (INAA) are the most common presentation. Salmonella (non-typhi), Staphylococcus aureus, Streptococcus spp, and Escherichia coli are the most identified pathogens.
Other microorganisms can be isolated such as Mycobacterium tuberculosis, Treponema pallidum, Pneumococcus, and Haemophilus influenza.
Other rare causes of aortitis have been identified such as drugs, granulocyte colony stimulating, chemotherapy, radiation therapy, and immunotherapy. As such, intravesical BCG immunotherapy, which is now used in the treatment of in situ bladder carcinomas, can lead to local BCG disease (BCGitis) caused by retrograde colonisation of the urinary tract. Disseminated BCG disease (BCGosis) is rare (3–5%); it can spread through lymphatic or haematogenous pathways
This is the report of a rare case of aortic BCGitis treated in a tertiary care centre.
Report
A 74 year old man was admitted to the hospital with fatigue, loss of consciousness, and acute on chronic renal failure (creatinine level 228 μmol/L, blood urea nitrogen [BUN] 13.4 mmol/L). Blood samples also showed hypercalcaemia (2.97 mmol/L), increased lipase 138 UI/L (3 × N), and a cholestatic pattern (11 × N ƔGT and 6 × N alkaline phosphatase). He was an active smoker, with a history of coronary artery disease treated by double aortocoronary bypasses (in 2018) with persistent occlusion of the right coronary artery, in situ bladder cancer treated with BCG therapy (in 2019), and chronic renal insufficiency (since 2018).
A few months before his presentation, he showed generalised fatigue, loss of appetite with weight loss, lumbar pain, and deterioration of renal function. A positron emission tomography/computed tomography (PET/CT) scan revealed a 5 cm right latero-aortic heterogeneous mass extending to the right edge of the diaphragm, with increased uptake on the right border of the visceral abdominal aorta (SUVmax 11) associated with multiple retroperitoneal lymph node formations of less than 1cm and tissue infiltration with a necrotic centre located at the level of the right posterior inframediastinal space (Fig. 1A). Another hypermetabolic focus was found on the right edge of L5 – S1 (SUVmax 7.1), with osteolysis of the upper plate of L4 (Fig. 1B). Magnetic resonance imaging did not show any signs of infectious spondylodiscitis and confirmed the presence of a rapidly expanding pararenal aortic pseudoaneurysm (Fig. 1C).
Figure 1Pre-operative imaging of a 74 year old patient with aortic BCGitis. (A) Positron emission tomography computed tomography (PET/CT) revealed increased uptake on the right border of the visceral abdominal aorta. (B) A non-contrast CT scan showed a 5 cm right latero-aortic heterogeneous mass (arrow) extending to the right edge of the diaphragm, associated with multiple retroperitoneal lymph node formations of less than 1cm. (C) Magnetic resonance imaging confirmed the presence of a rapidly enlarging pararenal aortic pseudoaneurysm (arrow).
After a multidisciplinary team meeting discussion, incorporating vascular surgeons, infectious disease specialists, microbiologists, nuclear physicians, and anaesthetists, the diagnosis of rapidly expanding INAA was suspected
and the patient was considered at high risk of rupture; exclusion of the aortic pseudoaneurysm was advised as soon as possible. Because of his past medical history, he was too high risk for open surgical repair. Hence, endovascular treatment was selected. A custom made fenestrated endograft could not be considered because of the manufacturing delay, thus, a four vessel physician modified endograft (PMEG) was created to exclude the aortic aneurysm and to preserve his visceral and renal vessels using a ZDEG-28-80 graft (Cook Medical, Bloomington, IN, USA). This Zenith TX2 Dissection Endovascular Graft with Pro-Form is a straight module (tapered or double tapered components are also available), usually indicated for the endovascular treatment of patients with Type B aortic dissection. It is a polyester based graft knitted on nitinol stents with gold markers but no barbs. The diameters range from 20 to 34 mm (20 Fr) and from 36 to 42 mm (22 Fr) and stent lengths are 80, 120, 180, and 185 mm. The modification was carried out with a cautery pen and the single loop portion of an Amplatz Goose Neck Snare kit (Medtronic, Minneapolis, MN, USA) sutured around the fenestration with CV5 Gore-Tex ties (Fig. 2A) and silastic laces for re-sheathing. Device modification lasted 25 minutes.
Figure 2Intra-operative imaging of endovascular exclusion of aortic BCGitis using a four vessel physician modified device. (A) The aortic graft was unsheathed under sterile conditions on a side table. Fenestrations were created using a cautery pen; a radiographic marker (the single loop portion of an Amplatz Goose Neck Snare kit; Medtronic/Covidien) was sutured around the fenestration with CV5 Gore-Tex ties. (B) CO2 angiography confirmed the presence of a saccular pseudoaneurysm on the lateral aspect of the pararenal aorta (∗). (C) Radiography was performed before implantation to confirm marker visibility and orientation. (D) Final CO2 angiography showed patency of all four target vessels and exclusion of the pseudoaneurysm.
The procedure was performed under general anaesthesia and systemic heparinisation (0.5 mg/kg). CO2 angiography confirmed the presence of a saccular pseudoaneurysm on the lateral aspect of the pararenal aorta (Fig. 2B). Radiography was performed before implantation to confirm marker visibility and orientation (Fig. 2C). The fenestrations were targeted through a femoral approach using a 0.035 inch Terumo hydrophilic guidewire (Terumo Europe, Leuven, Belgium), which was switched for a Rosen guidewire (Cook Medical) to deliver a 7F guiding sheath (KCFW; Cook Medical) into the target vessel and deploy an Advanta V12 of 9 × 38 mm for the superior mesenteric artery, 6 × 22 mm for the right renal artery, 7 × 22 mm for the left renal artery, and 10 × 38 mm for the coeliac trunk.
After the aortic aneurysm's exclusion, direct aneurysm sac guided aspiration (DASGA)
was performed by interventional radiologists for microbiological diagnosis as well as a hepatic biopsy. Specimens were sent to bacteriology, mycology, and pathology; autoimmune and infectious tests were also performed. Results came back negative except for hepatic histology showing granulomatous hepatitis with epithelioid and gigantocellular granulomas with central necrosis suggesting a hepatic location of BCGitis. As such, the patient was considered to have experienced organic acute renal failure and hypercalcaemia secondary to this granulomatous disease. Anti-tuberculous therapy was initiated with rifampicin 600 mg/d + isoniazid 200 mg/d + ethambutol 1 g/48h. The patient was discharged home on day 21 post-surgery on dual antiplatelet therapy for three months followed by lifelong single antiplatelet therapy. Check CT angiography was satisfactory with complete exclusion of the pseudoaneurysm and patency of all four target vessels (Fig. 3A and B). Six and twelve month PET/CT scans showed persistent uptake at the level of the excluded aneurysm (SUVmax 7.5; Fig. 3C and D) and confirmed thrombosis of the aneurysm sac. The patient was doing well clinically and gaining weight, indicating resolution of the disseminated infection. Re-evaluation is intended in six months' time. He continues to receive isoniazid and rifampin for chronic suppression with a plan for the use of an antibiotic regimen indefinitely.
Figure 3Post-operative imaging after endovascular exclusion of aortic BCGitis using a four vessel physician modified device. (A) Computed tomography (CT) angiography showed complete exclusion of pseudoaneurysm and patency of all four target vessels on axial slices. (B) 3D reconstruction. (C) Six month positron emission tomography computed tomography (PET/CT) showed persistent uptake at the level of the excluded aneurysm. (D) Twelve month PET/CT showed comparable results.
totalling 60 patients and revealing a high rate of septic recurrence (56%). The mean age was 71.3 ± 14 years with an average time since the last intravesical instillation of 20.5 ± 18 months. The majority (92.9%) of patients had no prior aneurysm and the abdominal aorta was involved predominantly (71.7%). The clinical and imaging presentations varied as for any INAA. Conservative treatment, open surgery, and endovascular treatment were given to 10%, 68.3%, and 21.7% of patients, respectively. The in-hospital mortality rate was 40%, 24.4%, and 15.4%. Among patients treated endovascularly, 61% had a recurrent infection (vs. 36.5% for open repair), 62.5% of whom required re-intervention (vs. 80% for open repair). Antituberculosis multidrug therapy was initiated in 90.6% of patients for an average length of 9.0 ± 5.9 months. No established consensus exists in terms of treatment options and outcomes either in healthy or immunodeficient patients. It ranges from simple discontinuation of BCG immunotherapy to a combination of antituberculosis drugs and corticosteroids.
Disseminated Bacillus Calmette-Guérin (BCG) infection with pulmonary and renal involvement: a rare complication of BCG immunotherapy. A case report and narrative review.
An antituberculosis treatment is considered necessary, usually in parallel with surgical treatment, and a two month course of isoniazid plus rifampicin plus ethambutol followed by at least seven months of isoniazid plus rifampicin has been described.
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
Nonetheless, most of the studies have focused on BCG lymphadenitis even though the highest attributable mortality rate of 15% is observed following vascular complications.
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
on BCG infection following intravesical instillation reported that granulomatous hepatitis, as well as penile lesions, and lung BCG infection tend to be early complications. Hence, approximately 2.9% of BCG treated patients discontinue immunotherapy due to a genito-urinary or systemic BCG related infection. However, the involvement of remote organs is uncommon and BCG infection could be related to a traumatic pre-procedure urethral catheterisation, which may impact men more frequently than women. Besides, vascular, testicular, muscular, and osteoarticular complications tend to appear later on. In the present case, instillations were stopped more than a year ago, and in the meta-analysis, the median time before occurrence was 52 weeks (IQR 20, 104; n = 65).
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
As such, vascular surgeons should be aware that BCG aortitis and vascular (endo)graft infections may occur up to some years after the last BCG instillation.
Diagnosis is difficult as serological tests and cultures fail to identify Mycobacterium bovis in approximately 60% of cases,
and the time between intravesical treatment and the onset of infective complications can vary. Microbiological data can be obtained in up to 83.6% of patients with vascular involvement with late occurring infectious complications
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
but for that purpose, mycobacterial testing should be mandatory in surgical samples. In patients where a microbiological diagnosis cannot be obtained, histology can show epitheliogigantocellular granulomas with or without caseous necrosis in about 40% of the biopsies and is crucial for diagnosis. In the present case, liver biopsy was indeed contributory, and a meta-analysis showed that more than one organ is involved in up to 28% of cases.
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
showed an association between lung, liver, and bone marrow complications on one side and vascular, muscular, and osteoarticular complications on the other, the link between liver and vascular complications was statistically significant (p = .005).
Regarding the management of INAA, the present authors preferentially offer open surgery with debridement of infected tissue, unlike others who have adopted an endovascular first strategy.
In the event of a contraindication, management is discussed on a case by case basis and, given the comorbidities and burden of a thoracophrenotomy for visceral aorta reconstruction, an endovascular approach seemed reasonable. Thereby, the only option for vascular documentation was the use of DASGA, which has mostly been studied for common bacteria but can be contributory in up to 81% of cases.
Infectious BCG complications after intravesical BCG administration for in situ bladder carcinomas can lead to both liver and aortic BCG infection. In the present case, the patient required an endovascular repair to prevent the risk of aortic rupture. The lack of positive microbiological data should not discourage clinicians from considering BCG infection, and histology showing granulomas is often crucial for a definitive diagnosis. Clinical suspicion of vascular BCG infection should be kept in mind even if several months or years have passed since the last BCG instillation. The management of this specific presentation mainly differs from the other forms of INAA by the type and length of antimicrobial treatment.
Disseminated Bacillus Calmette-Guérin (BCG) infection with pulmonary and renal involvement: a rare complication of BCG immunotherapy. A case report and narrative review.
BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review.
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