Pseudoaneurysm of the ascending aorta: case report of a donor-derived Pseudomonas infection in a heart transplant recipient

Background Mycotic aortic pseudoaneurysm is a rare complication after heart transplantation (HTX) with remarkable mortality. Intrathoracic infection is a well-documented predisposing factor for this disease. Staphylococcus aureus, Pseudomonas aeruginosa or Candida species are commonly isolated from resected specimens of the pseudoaneurysms. We demonstrate a unique case of mycotic pseudoaneurysm caused by presumably donor-derived Pseudomonas infection in a heart transplant recipient. Case presentation Our 67-year-old male patient treated with diabetes mellitus underwent HTX. The donor suffered from epiglottic abscess and pneumonia with known microorganisms including Pseudomonas, therefore both the donor and recipient received targeted antimicrobial therapy and prophylaxis. Five months after the uneventful HTX, lab test of the asymptomatic patient showed moderate, increasing C-reactive protein level without obviuos source of infection. Chest computed tomography showed a large (90 mm) saccular dilatation of the tubular portion of ascending aorta. Urgent surgical intervention identified a pseudoaneurysm, histological examinations and cultures of the resected aorta verified Pseudomonas aeruginosa aortitis, while all blood cultures remained negative. Retrospective interrogation of other transplanted organs of the donor supported donor-derived infection as the transport fluid of the right kidney grew Pseudomonas. The patient received 3 weeks of ceftazidime followed by 7 months of oral ciprofloxacin therapy. One year after the operation the patient was asymptomatic with normal inflammatory markers. Conclusions Donor-derived infection is a rare but potential cause of aortitis. Early diagnosis, surgical intervention and adjuvant antibiotic therapy seem to be the keys to successful management of mycotic pseudoaneurysms after HTX.


Background
After open heart surgeries, pseudoaneurysms of the thoracic aorta may develop from cannulation sites, suture lines or anastomotic sites [1]. Microorganisms tend to localize at the sites of previous injury in the wall of the vessel which predisposes to the formation of infected (or so called mycotic) pseudoaneurysms Open Access *Correspondence: kuglerszilvia92@gmail.com 1 Heart and Vascular Center, Semmelweis University, 68 Városmajor Street, 1122 Budapest, Hungary Full list of author information is available at the end of the article [2]. After heart transplantation (HTX), immunosuppression renders patients vulnerable to infection, which may lead to increased risk for aortic suture line insufficiency and the formation of mycotic pseudoaneurysms compared to immunocompetent individuals. Resected specimen of the mycotic ascending aortic pseudoaneurysms of heart transplantat patients frequently grows Staphylococcus aureus, Pseudomonas (P.) aeruginosa or Candida species. Based on literature data discussed in details below, two-thirds of patients recover after treatment. Despite the potentially fatal outcome of these complications, there are some controversial issues regarding the optimal surgical and antibiotic treatment.
We describe the case of an almost asymptomatic patient in whom a P. aeruginosa pseudoaneurysm of the ascending aorta developed five months after HTX at the aortic suture line. In this case no obvious concomitant infection was found at the patient and donor-derived infection is suspected. To the best of our knowledge, this is the first case, in which a mycotic aortic pseudoaneurysm was formed due to a probably donor-derived P. aeruginosa infection. We demonstrate the diagnostic process, discuss the antibiotic management and surgical treatment and also review the relevant literature.

Patient information
A 67-year-old man who had undergone orthotopic HTX 5 months before was admitted to our clinic for a surveillance endomyocardial biopsy (EMB) in perfect physical condition and asymptomatic. There was no history of fever episodes, other symptoms of infection, dyspnea, chest pain or malaise.
His medical history is significant for hypertension and chronic renal failure, the etiology of end stage heart failure was dilated cardiomyopathy with non-significant coronary stenosis. Brain death of the 31-year-old donor developed after a successful reanimation from a respiratory and cardiac arrest which was caused by an epiglottic abscess. The donor was septic with fever and high procalcitonin level (maximum 16 ng/ml). Cultures of the abscess grew Klebsiella aerogenes, Enterococcus faecalis, Staphylococcus aureus, Hafnia alvei, Finegoldia magna, Prevotella bivia and Prevotella oris. Chest x-ray and ultrasound showed right sided basal pneumonia. Microbiological examination of bronchoalveolar lavage fluid revealed the presence of Candida kefyr and multisensitive P. aeruginosa (results were validated on the day after transplantation). Donor received initial ceftriaxone therapy for 6 days (2000 mg once daily) that was changed to imipenem/cilastatin (500 mg four times daily), given for the last 24 h before donation.
Immunosuppression of the patient consisted induction therapy (3-day course of antithymocyte globulin and high-dose methylprednisolon) and triple maintenance immunosuppressive regimen including methylprednisolone (8 mg once daily), tacrolimus (aiming a trough level of 10-15 ng/ml in the first 3 months, then 8-10 ng/ ml) and mycophenolic acid (720 mg twice daily). Perioperative prophylaxis considering the microbiology culture results of donor consisted of meropenem (1000 mg three times daily) and vancomycin (1000 mg twice daily), given for 48 h. The postoperative course was uncomplicated. Transthoracic echocardiographies (TTE) revealed good graft function with normal estimated pulmonary artery systolic pressure. No rejection episodes could be found with surveillance endomyocardial biopsies.
Retrospectively, outcomes of other transplanted organs were interrogated from Eurotransplant. Liver, both kidneys, vascular homografts and connective tissue were explanted from the same donor. Transport fluid of the right kidney grew Pseudomonas, therefore the recipient of this organ received piperacillin/tazobactam prophylaxis. Preservation fluids of other organs were not cultured. Neither the recipient of the left kidney, nor liver recipient received any anti-Pseudomonas prophylaxis. No donor-derived infection was reported after transplantation of left and right kidneys, liver and connective tissue. Vascular homografts were discarded for safety reasons.

Clinical findings
At the beginning of June, the patient was scheduled for a regular EMB procedure. He presented with no symptoms except of a gradual weight loss of 15 kg (19% of his initial body weight) during 4 months. Physical examination was unrevealing. His blood pressure had been in target range for several weeks. No fever or subfebrility was detected.
TTE showed good graft function without any relevant abnormalities. Histological analysis of the EMB showed no rejection. Nor chest x-ray, neither abdominal sonography showed any relevant abnormalities. To identify the source of inflammation, a chest and abdominal computed tomographic (CT) scan was performed. This revealed a large, irregular, saccular dilatation of the tubular portion of ascending aorta with a maximum diameter of 90 mm (Fig. 1a, b).

Therapeutic intervention
Based on chest CT findings, an urgent surgical intervention was performed on the following day. Before performing median resternotomy, the left femoral artery was canulated through an 8 mm dacron vascular prosthesis for arterial line of cardiopulmonary bypass (CPB), to ensure the safety of patient in case of a pseudoaneurysm rupture. Myocardium protection was provided by antegrade Custodiol cardioplegia. After aortic crossclamp, the aortic pseudoaneurysm ( Fig. 2a) was opened. We identified the rupture of the former aortic polipropilene running suture (Fig. 2b), which could be the basis for the pseudoaneurysm formation between the donor and the recipient aorta. The tissue quality of both donor and recipient aorta seemed to be normal macroscopically. However, the tissues where the pseudoaneurysm wall attached to the donor aortic wall contained purulent-like debris, this was sent for microbiology examination. We resected the pseudoaneurym thoroughly and performed an aorto-aortic interposition between the recipient's distal ascendent aorta and donor's sinotubular junction with a 28 mm dacron vascular prosthesis (Fig. 2c). CPB time was 78 min, aortic cross clamp time was 48 min.
The patient recovered from surgery uneventfully. TTE showed unchanged graft function. No decline in renal function was detected.
Histologic evaluation of the resected pseudoaneurysm and aortic walls of the recipient and donor showed infectious aortitis, but no pathogenes could be identified. However, cultures of the resected specimens grew multisensitive P. aeruginosa. Serial blood cultures and urine culture were repeatedly negative.
The patient received 18 days of intravenous treatment of ceftazidime (2000 mg three times daily) followed by 7 months of oral ciprofloxacin (500 mg twice daily) from the day of discharge. The targeted antibiotic therapy resulted in significant decrease in CRP level.
In the early postoperative period mycophenolic acid therapy was transiently stopped and reinitiated in a reduced dose when inflammatory markers decreased. Tacrolimus and steroid regimen was maintained.

Follow-up and outcome
At follow-up examinations the patient was doing well without fever, TTE-s showed no abnormalities and CRP level remained normal. Blood pressure could be kept in target range. EMB-s showed no sign of rejection.
19 days and 7.5 months after the surgery chest CT angiograms showed intact interposition graft of the ascending aorta with no sign of recurrent aortic pseudoaneurysm (Fig. 3). Based on this finding and the continuously normal inflammatory markers of the patient, we decided to discontinue the oral ciprofloxacin therapy almost 8 months after the operation.
At his latest follow-up one year after the operation the patient is still asymptomatic with normal inflammatory markers.

Discussion and conclusions
Mycotic pseudoaneurysms of the ascending aorta are rare complications after cardiac surgery and are caused by growth of microorganisms in the vessel wall. The name mycotic aneurysm was coined by Osler to describe aneurysms associated with bacterial endocarditis [3]. These were noted to have the appearance of "fresh fungus vegetations", however, the majority of mycotic aneurysms are caused by bacteria. Immunosuppression is a major predisposing factor for this complication.
In our patient there was no evidence of any obvious concomitant infection. However epiglottic abscess and Pseudomonas pneumonia of the donor is notable. Although both the donor and recipient received broadspectrum antibiotic treatment, donor-derived Pseudomonas infection is possible as transport fluid of the donated right kidney also grew P. aeruginosa. P. aeruginosa grown from donor and recipient samples equally showed sensitivity for all antibiotics tested, which means they possessed a similar phenotype. Furthermore, the donor received only 24 h of adequate antibiotic therapy against Pseudomonas (imipenem/cilastatin) before the donation which might not have been long enough. These observations support the theory of donor-derived infection further. All available cases of Pseudomonas mycotic pseudoaneurysm in heart transplant recipients is summarized in Table 1. It is noteworthy that donor-derived  Pseudomonas mycotic pseudoaneurysm in a heart transplant recipient has never been described before. Possible symptoms of mycotic aortic pseudoaneurysms are malaise [4,18,22,28], chest [6,8,10,12,28,32] or back pain [6,19,23,33], dyspnea [17,25,27,30], hoarseness [21,30] or fever [4, 6, 8, 9, 12, 13, 17-19, 22, 23, 27, 31-33]. However, completely asymptomatic cases are also reported [25,26,34,37].
The patient demonstrated in the current case was almost fully asymptomatic except of an unexplainable weight loss. Weight loss as an usual general symptom of aortic pseudoaneurysm is reported in the literature as well and may be caused by the inflammatory state [11].
In the case of aortic pseudoaneurysm, common laboratory findings-also seen in our patient-are elevated serum CRP level and elevated white cell count, predominantly neutrophils [6,23,28,37]. Highly elevated erythrocyte sedimentation rate is also documented as an alarming sign [37].
It is obvious that the choice of antibiotic should be based on the culture and sensitivity of the isolated organism. Nevertheless, duration of intravenous and oral antibiotics in the case of P. aeruginosa aortitis after heart transplantation varies [7,14,18,19,[21][22][23] and permanent antibiotic therapy is recommended by some relevant literature datas [19,23]. Our strategy was the administration of targeted parenteral antibiotic treatment followed by continuous oral ciprofloxacin therapy. Systemic immunosuppression and synthetic aortic graft material are potential risk factors for recurrent graft infection, therefore, it is worth considering lifelong antibiotic treatment. However, it is also important to take care of potential side effects of permanent ciprofloxacin therapy including an increased risk of aortic aneurysm or dissection [38,39].
In conclusion, we presented a patient in whom a P. aeruginosa pseudoaneurysm of the ascending aorta developed after HTX. In this case no obvious concomitant infection was found at the patient and donorderived infection is suspected. This case demonstrates the importance of considering a mycotic pseudoaneurysm of the aorta in the etiology of unexplainable inflammation following HTX, even if the patient is almost asymptomatic. Surgical intervention and targeted antibiotic treatment are equally essential. P. aeruginosa as a causative organism may require long-term antibiotic therapy.  5 Outcomes of heart transplant patients diagnosed with ascending aortic mycotic pseudoaneurysms. Based on literature review, almost two-thirds of heart transplant patients recovered after treatment of their ascending aortic mycotic pseudoaneurysms. A sixth of patients died due to the pseudoaneurysm itself, an eighth of them suffered recurrence, while one fifteenth of patients died due to an unrelated cause. Among patients with recurrent pseudoaneurysms, ratio of recovery, pseudoaneurysm-related death and unrelated death was equal (49 cases reviewed, missing data in 4 cases)