Native-Valve Aspergillus Endocarditis: Case Report and Literature Review

Aspergillus endocarditis represents the second etiological cause of prosthetic endocarditis following Candida spp. On the other hand, native-valve endocarditis due to Aspergillus are anecdotally reported with increasing numbers in the last decade due to new diagnostic technologies such as polymerase chain reaction (PCR) on samples like valve tissue or entire blood. We performed a review of the literature presenting one case report observed at Pisa University Hospital. Seventy-four case reports have been included in a period between 1950–2022. Immunocompromised status (patients with solid tumor/oncohematological cancer or transplanted patients) was confirmed to be the main risk factor for this rare opportunistic infection with a high rate of metastatic infection (above all, central nervous system) and mortality. Diagnosis relies on serum galactomannan and culture with PCR on valve tissue or whole blood. Cardiac surgery was revealed to be a life-saving priority as well as appropriate antifungal therapy including b-liposomal amphotericin or new triazoles (isavuconazole). The endocarditis team, facing negative blood culture endocarditis affecting an immunocompromised patient, should investigate this difficult-to-treat pathogen.


Introduction
Aspergillus is a ubiquitous mold that has the ability to cause broad spectrums of clinical manifestations both in healthy and immunocompromised humans [1,2].
Endocarditis caused by Aspergillus spp. (AE) is an uncommon disease with a high mortality rate that usually develops in patients with a predisposing condition, such as immunocompromised status or previous cardio-thoracic surgery. The diagnosis and treatment of the infection is highly challenging, while the disease often foreshadows a poor prognosis [3].
In this article, we describe a case of native-valve Aspergillus endocarditis (NVAE) occurring in a middle-aged Caucasian woman without previous cardiac medical history nor known immunocompromised status and we performed a review of the available literature.

Case Report Description
In November 2021, a 74-year-old Caucasian woman was transferred from a secondary general hospital to Pisa University Hospital presenting with acute heart failure and cardiogenic shock in order to be evaluated by the cardiac surgery team. At first evaluation, a huge aortic valve vegetation was discovered upon cardiac ultrasonographic findings.
With regards to her medical history, she was a former smoker with untreated arterial hypertension and dyslipidemia, with no history of intravenous drug use.
Eight months earlier, she had undergone an atypical endoscopic resection of the lower lobe of the left lung for an adrenocorticotropic hormone (ACTH)-secreting neuroendocrine neoplasia that caused Cushing's syndrome with secondary diabetes.
The patient arrived at Pisa University Hospital sedated and in endotracheal intubation; laboratory data showed normal white blood cells count (8470/mcl) with absolute neutrophilia and lymphopenia (7340/mcl and 640/mcl, respectively) and increased plasma levels of C-reactive protein (CRP, 11.63 mg/dL) and procalcitonine (PCT, 5.53 ng/mL) as well as increased levels of nt-proBNP (17,531 ng/L), high sensitivity troponins (1084 ng/L), CPK-MB (22.2 U/L) and myoglobin (238 g/L). Microbiological sampling was performed and two sets of blood cultures were collected. Subsequently, an empirical antibiotic therapy with meropenem (3 g per day) and vancomycin (2 g per day) was started and the patient immediately (<3 h since transferal) underwent aortic valve replacement with a bioprosthesis Perimount Magna Ease 21 mm (Edward Lifesciences Corporation, Irvine, CA, USA); the native aortic valve was sent to the laboratory to perform microbiological culture.
On the 5th post-operative day, the patient was extubated with good clinical response. Inflammatory markers (CRP and PCT) showed a positive reduction; therefore, antimicrobial therapy with meropenem and vancomycin was continued. The patient was still treated in the ICU.
On the 7th post-operative day, the microbiology lab informed that a strain of Aspergillus fumigatus grew from a flap of the native aortic valve. The infectious diseases consultant ceased antibiotic therapy and antifungal therapy with liposomal B amphotericin (5 mg/kg per day) was started. Due to good clinical evolution, the patient was then transferred to the cardiac surgery ward. As part of endocarditis work up, abdomen ultrasonography found no signs of splanchnic embolization while a brain CT scan revealed signs of microembolizations to the central nervous system. At this point, intravenous Isavuconazole (200 mg per day after loading doses) was added as a combination therapy with liposomal B amphotericin.
On the 10th post-operative day, a control transesophageal echocardiogram was performed showing a bioprosthetic valve with no leakage or signs of dysfunction, nor vegetations.
On the 21st post-operative day, due to confirmed good clinical evolution and negative screening blood cultures, the patient was transferred to a rehabilitation hospital. During the rehabilitation period, antifungal treatment was continued with Isavuconazole.
After 18 days in the rehabilitation hospital, the patient presented with a subtle episode of dyspnea. She was admitted to a secondary hospital and required pleural drainage due to presenting with a bilateral pleural effusion. Urgently, an 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan was performed, revealing hypermetabolic uptake in the aortic bioprosthesis. This data was confirmed with a transesophageal echocardiogram showing the presence of a vegetation of 12 mm × 8 mm on the aortic valve bioprosthesis.
The same day, the patient was readmitted to Pisa University Hospital to be treated with surgical debridement of the prosthetic valve. Unfortunately, the patient died during the cardiac surgery re-intervention due to overwhelming vascular complications.

Materials and Methods
We conducted a Medline search for Aspergillus endocarditis using the terms "AS-PERGILLUS" and "ENDOCARDITIS" from 1950 to October 2022; we included case reports about native-valve endocarditis and mural endocarditis in patients without previous valve surgery. All prosthetic or device-related infections were excluded. We collected 74 case reports with an available original article. Table 1 shows the baseline and microbiological features, cardiac and systemic involvement, surgical treatment and outcome (alive status) as reported by the authors.

Discussion and Review of the Literature
This is a rare case of native-valve Aspergillus endocarditis in a woman without previous cardiac medical history nor ongoing immunosuppression, which is one of the main risk factors to develop invasive aspergillosis (IA) [1,2]; this is in line with our review's finding where 64% (48 out of 74) of the patients with NVAE had underlying immunosuppressive conditions, mainly hematological malignancies (28%) and solid organ transplantation (SOT) (17%).
Nearly half of the cases of NVAE in SOT patients occurred in lung transplantation (six out of thirteen patients), which represents one of the most immunomodulated medical conditions. We suppose that our patient's risk factors could have been previous endothoracic surgery for neuroendocrine cancer and diabetes due to ectopic ACTH secretion. Solid tumors and diabetes are considered predisposing conditions to develop invasive fungal disease (IFD) [67,68], that in our review have been found in 4% and 5% of the patients, respectively.
With the exception of six lung-transplanted patients, in the report series, none of the patients had a history of lung surgery but 8% had undergone previous heart surgery, suggesting that thoracic intervention generally may be a risk factor to develop NVAE.
At what we know, 6% of the patients had no known comorbidity; they were all males, between 35 and 66 years of age [5,9,34,46,57].
Our patient had vegetation involving the aortic valve. We found that the aortic valve alone is less commonly involved than the mitral valve alone (13% vs. 42%, respectively) and, as a remarkable finding, native multi-valve endocarditis affected about 10% of the patients included in the review. More than half of these patients had hematological malignancies, while interestingly, about 30% of the patients had mural endocarditis, a known characteristic of AE [69,70].
Lung involvement was present in at least 40% of patients with NVAE, less than the proportion usually described in the literature about IA [1], and up to 70% of patients presented with embolization. Our patient had central nervous system (CNS) embolization and, consistently with our review, the CNS was found to be the most frequent site of embolization (54%) with a high burden of mortality with a one-year survival rate of 10%. In a teaching case, a patient that had recovered from NVAE with CNS embolization presented with a seizure 20 months after treatment, likely due to scar tissue replacement of the previous brain embolic abscess [52]. Visceral and intravascular embolization occurred in 21% and 12% of the reports, respectively.
The causative agent of our patient's endocarditis was A. fumigatus, the most common cause of IA [1]. According to our review, it is the most frequent fungal isolate (58%) followed by A. flavus (15%) and A. terreus (2%). Other species found to be involved in NVAO in immunocompromised hosts were A. niger, A. nidulans and A. udagawae.
Diagnosis of NVAE is often difficult and 10% of the cases in this review were diagnosed at post-mortem analysis. In our case, diagnosis was made by standard microbiological culture of the valvular flap, in line with our review's finding where in vivo diagnosis was made primarily by histological finding or cultural exam of pathological tissues. Aspergillus spp. were found mainly in valves (52% of cases) and emboli (16%), followed by abscesses and lung specimens such as biopsy or bronchoalveolar fluid (9%). In one case, the growth of A. fumigatus from pleural and pericardial fluid foretold the onset of NVAE about one year in advance prior to clinical presentation and diagnosis [43].
In our case, the blood cultures were negative; this represents an important diagnostic challenge of AE as only 10% of the patients in the review had positive blood cultures, confirming that histological examination and culture of pathological tissues are essential exams to diagnose IA [71].
In this review, since 1998, Aspergillus spp. galactomannan has been tested in twentyfour cases; it was positive in sixteen cases (66%), five of whom had high serum levels of 1,3-B-d-glucan. Detection of antigenemia informed clinical choices in five cases of immunocompromised hosts with no other microbiological findings and three of them survived, confirming the reliable sensitivity of these markers in the diagnosis of IA in the context of immunosuppression [32,41,55,71,72].
In at least one case, suspicion of IA was confirmed by molecular methods on blood samples but the role of this method in the diagnosis of IA is still uncertain due to the lack of standardization [66,71]; an interesting use of polymerase chain reaction on blood samples is suggested in one case where it has been used to monitor antimycotic drug efficacy in a pediatric liver transplant recipient who had a favorable outcome without cardiac surgery [32].
In this review, NVAE has been confirmed to be a life-threatening condition with an overall mortality rate of at least 60%.
Our patient underwent surgical valve replacement. In our review, surgical treatment was performed in 58% of patients with a higher survival rate in patients that underwent cardiac surgery rather than those who did not receive surgical treatment (34% vs. 22%, respectively). It was performed for 15 out of the 22 (68%) surviving patients. These findings are in line with most important guidelines that recommend surgical intervention in cases of fungal endocarditis [73,74].
Triazoles and polyenes are the main medical options for IA and their use is strictly tied to fungal species, drug susceptibility, host characteristics and therapeutic drug monitoring [71].
On the basis of fungal growth on the valvular flap, an antimycotic therapy with liposomal B amphotericin was initially started and then implemented adding isavuconazole after the radiological finding of microembolization to the CNS. In our review, these antifungal agents were used in the same patient in eleven out of the twenty-two cases that had favorable outcomes, three of whom had not undergone surgical intervention; in eleven cases, voriconazole was used alone and in six of these cases, patients survived at 1 year, including a pediatric patient who did not undergo cardiac surgery and another patient reported to be on undefined oral therapy, while monotherapy of amphotericin B was administered in fifteen reports, nearly half of whom in the pre-liposomal and pre-triazoles era, with only two patients surviving [36,63].
In our review, eight cases of diagnosed IFD that underwent therapy occurred before 1997, a year during the early triazole era [75] in which the Food and Drug Administration (FDA) approved the commercialization of liposomal B amphotericin formulations [76], and only one patient survived. Since then, the overall survival rate in our review increased up to 35%.
Our patient underwent surgical valve replacement while not on antifungal therapy and died due to a relapse on the bioprosthesis while she was still taking appropriate antifungal therapy. Valve surgery is one of the main predisposing conditions to develop AE and in our review, at least four patients had relapses on their bioprostheses with unfavorable outcomes, three of whom were not on antimycotic therapy at the moment of surgical intervention. This finding, associated to our report, hints that prompt antifungal therapy may reduce the risk of relapses in AE, a high mortality event that can occur even more than one year from valve surgery [3,30].

Conclusions
Aspergillus endocarditis can occur on native valves and it is a life-threatening condition that requires prompt diagnosis. It should be suspected in negative blood culture endocarditis both in patients with underlying immunosuppressive conditions and in immunocompetent hosts. Diagnosis is not easy; the clinical context and biomarkers can guide the suspicion but confirmation with tissue histology and culture is fundamental.
The optimal approach is early treatment with surgical debridement and appropriate antifungal agents, mainly triazoles. Antifungal prophylaxis may be a strategy to reduce the incidence of this condition in immunocompromised patients with negative blood culture endocarditis that undergo valve surgery. Follow-up imaging after cardiac surgery should include a cardiac PET-CT scan at 3-6 months after the procedure, in order to decide safely to stop or continue the antifungal maintenance regimen. In some cases, life-long maintenance antifungal treatment is necessary. Despite the improvement of both diagnostic methods and antifungal drugs, timely diagnosis and appropriate treatment remains a major challenge of this fatal disease.
Funding: This research received no external funding.
Institutional Review Board Statement: Ethical review and approval were waived for this study (case report and review).