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Abstract
Background—Mycotic aortic aneurysm (MAA) is a rare and life-threatening disease. The aim of this European multicenter collaboration was to study the durability of endovascular aortic repair (EVAR) of MAA, by assessing late infection–related complications and long-term survival.
Methods and Results—All EVAR treated MAAs, between 1999 and 2013 at 16 European centers, were retrospectively reviewed. One hundred twenty-three patients with 130 MAAs were identified. Mean age was 69 years (range 39–86), 87 (71%) were men, 58 (47%) had immunodeficiency, and 47 (38%) presented with rupture. Anatomic locations were ascending/arch (n=4), descending (n=34), paravisceral (n=15), infrarenal aorta (n=63), and multiple (n=7). Treatments were thoracic EVAR (n=43), fenestrated/branched EVAR (n=9), and infrarenal EVAR (n=71). Antibiotic was administered for mean 30 weeks. Mean follow-up was 35 months (range 1 week to 149 months). Six patients (5%) were converted to open repair during follow-up. Survival was 91% (95% confidence interval, 86% to 96%), 75% (67% to 83%), 55% (44% to 66%), and 41% (28% to 54%) after 1, 12, 60, and 120 months, respectively. Infection-related death occurred in 23 patients (19%), 9 after discontinuation of antibiotic treatment. A Cox regression analysis demonstrated non-Salmonella–positive culture as predictors for late infection–related death.
Conclusions—Endovascular treatment of MAA is feasible and for most patients a durable treatment option. Late infections do occur, are often lethal, and warrant long-term antibiotic treatment and follow-up. Patients with non-Salmonella–positive blood cultures were more likely to die from late infection.
Introduction
Mycotic aortic aneurysm (MAA) was coined by Sir William Osler in 1885, but it is a misnomer for infection (usually bacterial) that degrades the aortic wall with subsequent aneurysm development.1 MAA is a rare but life-threatening disease, with an incidence of about 0.65% to 2% of all aortic aneurysms in Western countries2,3 and reportedly higher in east Asia.4,5 The disease carries a very poor prognosis because MAAs have a tendency to grow rapidly and to rupture; patients with MAA often have severe comorbidities, in particular immunodeficiency, and coexisting sepsis.6,7 Conventional surgical treatment with resection of the aneurysm, extensive local debridement, and revascularization by in situ reconstruction or extra-anatomic bypass is the gold standard but carries a high mortality and morbidity.8 Furthermore, the anatomic location of the aneurysm sometimes makes surgical repair very demanding, or even impossible.9
Editorial see p 2129
Clinical Perspective on p 2142
Endovascular aortic repair (EVAR) is a less invasive alternative to conventional open repair of MAA. A major disadvantage is that the infected tissue, including the aneurysm itself, is not resected, which may result in recurrent sepsis and infection of the endoprosthesis. However, EVAR is a less invasive treatment with reduced early mortality and morbidity, especially in high-surgical-risk patients. EVAR for MAA may be considered either permanent or a bridge to open surgery, allowing the patient to recover before definitive elective open surgery.
Reports on EVAR for MAA have shown promising results but only small single-center case series with limited follow-up have been published.10–13 The crucial question of durability therefore remains unanswered. The aim of this European multicenter collaboration was to study the durability of endovascular treatment of MAA, by assessing the late infection–related complications and long-term survival.
Methods
All patients treated endovascularly for MAAs at 16 European centers from 8 countries between 1999 and 2013 were identified. Participating centers are named in affiliations and shown in Figure 1.
Participating centers.
An MAA was defined as a combination of the following 3 criteria: (1) clinical presentation (pain, fever, sepsis, or concomitant infection), (2) laboratory tests (elevation of inflammatory markers like C-reactive protein and white blood cells, or positive cultures), and (3) radiological findings on computed tomography (CT) or MRI (rapid expansion of aneurysm, saccular aneurysm, multi-lobular aneurysms, eccentric aneurysms, periaortic gas, and periaortic soft tissue mass). An infection-related complication was defined as recurrent sepsis, graft infection, aorto-enteric fistula, or recurrence of a new MAA, in the same or at a different location.
All cases were retrospectively reviewed, applying a common study protocol (see the online-only Data Supplement) including data on (1) patient characteristics and clinical presentation (sex, age, medical history, immunodeficiency [including comorbidities and treatments associated with relative immunodeficiency], symptoms, concurrent infection, blood tests and microbiological cultures), (2) aneurysm characteristics (aneurysm status, location, CT-findings; rapid expansion, saccular, multilobular, periaortic gas, periaortic mass), (3) treatment (endovascular approach, extra-anatomic hybrid procedure, bridge to open repair, antibiotic treatment [ABx]), and (4) follow-up time, outcome, and complications. All study protocols were sent to Uppsala for a secondary review (K.S. and A.W.). Cases treated with hybrid repair (combination of endovascular and open repair) were included if a stent graft was deployed in the infected field, thus leaving the infected aneurysm in situ. Primary graft infections, aorto-enteric fistulae, and graft-enteric fistulae were excluded, as well as cases that did not meet the predefined criteria of an MAA.
Survival analysis was performed according to Kaplan–Meier. Univariable Cox regression risk factor analyses were performed using a statistical software package (SPSS 22, IBM Corporation, Armonk, NY). In the risk factor analysis the microbiological cultures were divided in 3 subgroups: negative, Salmonella-positive, and non-Salmonella–positive cultures (all others). The cumulative incidence of infection-related death accounting for the competing risk of death of other causes, and the cumulative incidence of reintervention (open or endovascular) with the competing risk of all-cause death, was calculated using the package cmprsk in R14 (Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org). A P value <0.05 was considered significant.
Results
A total of 134 cases were identified, and 11 were excluded: primary graft infections (n=6), primary aorto-enteric fistulae (n=2), and when an infectious pathogenesis could not be verified (n=3). Thus, a total of 123 patients treated for an MAA by means of endovascular technique were included in the study. Table 1 shows demographic, clinical, laboratory, and treatment characteristics, and Table 2 concurrent infections and blood cultures. The mean duration of ABx treatment was 30 weeks (range 1–420), and 32 patients (26%) had ABx-treatment continuously throughout the study period. Eighty-two patients (67%) were treated with multiple ABx.
Demographic, Clinical, Laboratory, and Treatment Characteristics
Concurrent Infections and Blood Cultures
Outcome
The mean follow-up time was 35 months (median 20, range 1 week to 149 months). According to a Kaplan–Meier analysis 1-month survival was 91% (95% confidence interval, 86% to 96%), 3-month 86% (80% to 92%), 1-year 76% (67% to 83%), 5-year 55% (44% to 66%), and 10-year 41% (28% to 54%; Figure 2). Causes of deaths are presented in Table 3. Kaplan–Meier survival curves for different subgroups are presented in Figure I in the online-only Data Supplement.
Causes of Death
Kaplan–Meier 10-year survival curve of 123 patients treated for a mycotic aortic aneurysm by means of endovascular technique.
A total of 33 patients (27%) developed an infection-related complication, of whom 23 (70%) died (19% of the total cohort; Table 4). Thirty percent (7/23) of these occurred within the first 30 days, 52% (12/23) within 90 days, and 82% (19/23) within 1 year. Four patients had a fatal infection-related complication after 1 year; 1 endograft infection after 16 months, 1 graft-enteric fistula after 35 months, 1 new MAA after 36 months, and 1 sepsis after 54 months. In 9 of the patients a fatal recurrent infection-related event occurred after discontinuation of ABx-treatment (mean time 31 weeks, range 10–52). Figure 3 illustrates the cumulative incidence of infection-related death, with death of other causes as competing risk; 16.4% (95% CI, 8.0–20.2) at 1 year, 21.7% (10.4–24.1) at 5 years, and 21.7% (10.4–24.1) at 10 years.
Infectious Complications After Endovascular Repair of MAA
Cumulative incidence of infection-related death, with death of other causes as competing risk.
In a Cox-regression model all-cause mortality was significantly associated with age (hazard ratio [HR], 1.0; 95% CI, 1.0 to 1.1; P=0.033) and non-Salmonella–positive blood culture (HR, 2.0; 95% CI, 1.1–3.6; P=0.015), whereas a negative association was seen for negative blood culture (HR, 0.5; 95% CI, 0.3 to 1.0; P=0.042; Table 5). Within the group of non-Salmonella–positive blood culture the survival was similar for Staphylococcus, Streptococcus, and miscellaneous organisms. The 5-year survival of patients with non-Salmonella–positive blood culture was 41% (95% CI, 26% to 56%), with infection-related complications as the cause of death in 50% (14/28), of which 9 (64%) occurred after 90 days. In the subgroup of 15 patients with Salmonella-positive blood culture, 4 of 6 deaths occurred within 90 days, and the 5-year survival among those surviving 90 days was 90% (91% CI, 71% to 100%).
Univariable Cox-Regression Analysis of Long-Term Mortality Among 123 MAA
The 5-year survival of patients with immunodeficiency was 40% (95% CI, 20% to 60%), with infection-related complications as the cause of death in 64% (16/25), of which 9 (56%) occurred after 90 days. The subgroup of 12 patients with periaortic/intrathrombus gas on preoperative CT scan had a 5-year survival rate of 36% (95% CI, 0% to 72%); all deaths were infection-related, of which 4 (67%) occurred after 90 days.
Six patients (5%) were later converted to open repair within a time span of 3 days to 15 months, as a result of graft infection (n=2), aorto-enteric fistula (n=1), type I endoleak (n=1), recurrent MAA (n=1), and unknown cause (n=1). Two of these patients survived the open repair conversion. Thirteen patients (11%) required endovascular reoperation from 1 day until 24 months of follow-up, 9 for type I endoleak, and 7 successfully treated with stentgraft extension and one with balloon-dilatation only. One patient with a type I endoleak died from cardiac arrhythmia during the initial phase of the attempted reintervention. Two patients were successfully treated for type II endoleak; 1 with coiling and 1 with onyx embolization. Two patients had a type III endoleak; 1 presented with rupture after 24 months and was successfully treated with a cuff. The other presented with rupture after 18 months, was treated with a stentgraft extension, but died from multiorgan failure after 6 weeks. Figure 4 illustrates the cumulative incidence of reoperation (open or endovascular) with all-cause death as competing risk; 13.4% (95% CI, 10.3–23.8) at 1 year, 16.6% (14.2–30.4) at 5 years, and 16.6% (14.2–30.4) at 10 years.
Cumulative incidence of reintervention (open or endovascular), with all-cause death as competing risk.
Discussion
MAA is a complex disease with challenging treatment and poor survival. The largest study of open surgical treatment of MAA was published in 2011 by Yu et al15 from Taiwan and consisted of 54 patients, and the largest study on endovascular treatment, published in 2012 by Sedivy et al13 from The Czech Republic, included 32 patients. The disease is difficult to study because of its rarity, therefore large-scale multicenter collaborations are necessary. This European multicenter study of MAA is the largest ever, and the aims were to assess the durability of endovascular treatment, including late reinfection. The main findings of this study are (1) good short-term outcome (91% survival at 30 days), (2) a significant number (19%) of fatal infection-related complications, mostly occurring during the first postoperative year, (3) a relatively good long-term outcome (55% survival at 5-years) with few serious late infection–related complications, and (4) adverse long-term outcome among those with a non-Salmonella–positive blood culture.
Most reports on open repair show a much worse outcome, with short-term mortality rates of 20% to 40%6–8,15–18 and significant short- and long-term morbidity related to the operation.7,9,19 Reports on long-term outcome after open repair are scarce. The reported 2-year survival is about 60%,8,16 and a 5-year survival rate of 35% was reported from a German single-center study on 33 patients.6 Late graft infections occurred in 7% to 10% of the cases,8,15,17 and extra-anatomic bypass had worse outcome than in situ reconstructions.6,17 A minimally invasive approach by means of endovascular techniques makes it possible to treat patients unsuitable for major open surgery. In this report a majority of the patients had severe, multiple comorbidities, hostile anatomy, ongoing sepsis, or presented with rupture. A similar case mix was not seen in previous reports on open repair, making comparison difficult.
Considering the complexity of MAA patients, the observed outcome of MAA stent graft recipients may be considered comparable with the results seen after EVAR/thoracic endovascular aortic repair in general. In a Swedish study of 946 patients with noninfected abdominal aortic aneurysm treated with EVAR 1987 to 2005, the 5-year crude survival was 65% after intact abdominal aortic aneurysm and 54% after ruptured abdominal aortic aneurysm, with a mean age of 74 and 75 years, respectively.20 In a U.S. Medicare study of 2732 patients with descending thoracic aortic aneurysm treated with thoracic endovascular aortic repair from 1998 to 2007, the corresponding survival rates were 62% and 23%, with a mean age of 76 and 78 years.21 However, an important difference between patients with a primary infected aneurysm and patients with a degenerative noninfected aneurysm is that the former are considerably younger (mean 69 years versus 74–78 years), and also probably have less comorbidities related to peripheral vascular disease and atherosclerosis.
Salmonella aortitis is a known complication of infection with Salmonella, which has a proclivity to adhere to vascular endothelium, especially if it is diseased by atherosclerosis.22 Marked geographical microbial differences exist with Salmonella enteritidis being more dominant in Europe, but less common in Asia, where the variety of circulating serotypes are greater.23 Salmonella infections are much more common in East Asia where most MAAs are caused by nontyphoidal Salmonella.8,14,16,24,25 Salmonella-related aneurysms are known to have a fast disease progression with risk of early rupture.8,9,26 After the initial postoperative period with high mortality, Salmonella-positive patients had a favorable long-term outcome in the present report, which may be attributed to the effectiveness of modern ABx.22 Non-Salmonella–positive blood culture was the main factor associated with serious late complications in the present report, an observation supported by previous smaller reports.8,19,26,27
The duration and choice of ABx-therapy is an important matter for debate. Some authors recommend parenteral or oral ABx for at least 6 weeks.11 A significant proportion of those developing late fatal infection-related complications did so after discontinuing ABx therapy. Most recurrent infections occurred within the first year, predominately within the first 6 months. This suggests that long-term ABx therapy, for at least 6 to 12 months and possibly for life, is a prerequisite for successful endovascular treatment of MAA. Empirical ABx treatment effective against Staphylococcus aureus and Gram-negative rods, such as Salmonella, should be initiated in cases which are culture negative.
Although the present study shows that endovascular treatment of MAA is feasible and for most patients may be a durable treatment option, late infection–related complications do occur and are often lethal. Patients with non-Salmonella–positive blood culture were at higher risk of late death and fatal infections complications, indicating a need for vigilant antibacterial treatment and follow-up in these cases. EVAR could be considered a palliative treatment option in these patients, or a bridge to later elective radical open surgery, once the patient has recovered from the initial emergency. However, this strategy was rarely adopted in this series. A few were converted to emergency open repair for life-threatening complications, whereas most patients were either too well to justify a major open procedure or were too fragile to withstand such an operation.
Limitations
The retrospective design of this study is a limitation with risk of selection bias. However, during the study time period only a handful of patients with MAAs were treated with open repair in the contributing centers, which suggests that this bias is minimal.
It is important to distinguish between primary infections of the native aorta (ie, an MAA) from secondary aortic infections, such as graft infections, aortoenteric fistulaes, as well as inflammatory aneurysms. The definition of an MAA, as an aneurysm with proven bacterial infection in the aortic wall, however, creates an inherent limitation in studies of this disease, especially when treated endovascularly where bacterial culture from the aortic wall cannot be obtained without risk. The difficulty in obtaining anaerobic cultures, and the fact that these patients often received early broad spectrum antibiotics, may explain the rate of positive cultures in the present report (67%), which is in line with previous reports on endovascular as well as on open repair.6,7,27,28 Consequently, microbiological cultures (blood or aortic tissue) may turn out negative, despite a high clinical suspicion of a MAA. Adding to the complexity of this issue, routine culture of abdominal aortic aneurysm wall during open surgery of clinically noninfected patients has been found to be positive in ≈14% to 37% of the cases.29,30 In these studies about 90% of the microorganisms were Gram-positive, and the authors concluded that positive cultures from aneurysm without rupture or signs of infection were not a risk factor for secondary graft infection and have no pathogenic significance or therapeutic implication. Thus, a positive culture (blood or aortic tissue) alone is not sufficient for the diagnosis MAA. Other symptoms/findings, such as clinical signs of infection and radiological findings of an atypical aneurysm, should support the diagnosis. In this report, as well as in most previous studies, patients were included based on a clinical diagnosis of MAA (supported by clinical presentation, hematological tests, culture, and CT findings). All cases included met multiple criteria for the diagnosis, minimizing the uncertainty of an infectious genesis.
With few events (deaths), the precision of estimates (hazard ratios) is poor and the power to detect risk factors with moderate effects is low. Thus, the current risk factor analysis is susceptible to type II statistical errors. It is also likely that a Cox model underestimates the effect (death) of a postoperative infection complication, by failing to account of possible time free of infection in those who later experience a postoperative infection. The timing (debut/ending) of postoperative infections (such as sepsis) are, however, difficult to define, for which it is difficult to use a time-dependent covariate approach.
Conclusions
Endovascular treatment of MAA is feasible and for most patients a durable treatment option. Late infection–related complications do occur, are often lethal, and warrant long-term antibiotic treatment and follow-up, especially in patients with non-Salmonella–positive blood culture. In those cases, EVAR could be considered a palliative option or a bridge to later elective open repair.
Acknowledgments
We gratefully acknowledge the assistance of Marcus Thuresson, Statistician, PhD, Statistician AB Uppsala, for reviewing the statistical analyses and performing competing risk analysis.
Disclosures
None.
Footnotes
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.114.009481/-/DC1.
- Received February 14, 2014.
- Accepted September 18, 2014.
- © 2014 American Heart Association, Inc.
References
CLINICAL PERSPECTIVE
Primary infectious (mycotic) aortic aneurysm is a rare but life-threatening disease. The disease carries a very poor prognosis because mycotic aneurysms have a tendency to grow rapidly and to rupture. Furthermore, patients often have severe comorbidities, are immunosuppressed, and have coexisting sepsis. Conventional surgical treatment with resection of the aneurysm, extensive local debridement, and revascularization by in situ reconstruction or extra-anatomic bypass is the gold standard but carries a high mortality and morbidity. In addition, the anatomic location of the aneurysm sometimes makes surgical repair very demanding, or even impossible. Reports on endovascular treatment for mycotic aneurysm have shown promising results, but only small single-center case series with limited follow-up have been published. The crucial question of durability therefore remains unanswered. The disease is difficult to study because of its rarity, and therefore large-scale multicenter collaborations are necessary. This European multicenter study, the largest ever on mycotic aortic aneurysm, shows that endovascular treatment of mycotic aortic aneurysms is feasible and, for most patients, a durable treatment option. However, late infection–related complications do occur and are often lethal, indicating a need for vigilant antibacterial treatment and follow-up.
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