Aspergillus spp. are ubiquitous, filamentous fungi with hyaline, septated, branched hyphae.
These molds have the capacity to cause several diseases in both healthy and immunocompro-mised hosts. Aspergillus spp. are the second most common fungal organism, after Candida spp., causing endocarditis in patients with previous valvular surgery ; this condition is discussed in the chapter on prosthetic valve endocarditis. Aspergillus spp., albeit much less commonly, can also cause endocarditis in patients without prior cardiac surgery. The two major manifestations of cardiac aspergillosis in the native heart are Aspergillus NVE and Aspergillus mural (non-valvular) endocarditis.
Aspergillus NVE is much less common than endocarditis involving prosthetic valves, with a review by Gumbo et al.  identifying 61 cases in the English literature. As with other forms of invasive aspergillosis, immunocom-promised status (defined as presence of hemato-logic malignancy undergoing chemotherapy, adminstration of large or prolonged doses of corticosteroids, solid-organ transplant recipient receiving anti-lymphocyte therapy) was a major risk factor for Aspergillus NVE . Advanced HIV, with marked CD4 T lymphocytopenia, also appears to be a risk factor .
The major clinical manifestations of Aspergillus NVE were fever (reported in 74% of cases), systemic embolization (69%), and a new regurgitant heart murmur (41%) [407,418]. Embolic phenomena frequently involved the central nervous system (brain, eyes), skin, and the aorta/large vessels [418,420]. Involvement of the brain can manifest with focal or general neurologic deficits. Ocular involvement manifests as endophthalmitis with sudden visual loss; this complication has been reported in 13% of cases . As a corollary, it has been suggested that any patient with Aspergillus endophthalmitis should be evaluated for endocarditis, which has been associated in up to 40% of cases . Skin involvement typically presents as subdermal nodules  or necrotic lesions ; either can serve as a substrate for biopsy that may allow for earlier presumptive diagnosis [418,420]. Vascular involvement can manifest as occlusive embolism, typically of large vessels (e.g., ilica, femoral, subclavian arteries) . Alternatively, Aspergillus spp., as a result of their angioinvasive properties, can rapidly seed vascular walls and create focal areas of weakness that lead to aneurysmal disease. These aneurysms can occur in multiple vascular beds (e.g., ascending aorta, circle of Willis, periph eral) and can subsequently rupture . Embolic disease to the kidney has been reported in 40% of cases . Local complications can also develop, including pancarditis and cardiac rupture .
The major species reported as causing Aspergillus NVE include A. fumigatus, A. flavus, A. terreus, and A. nidus [418,420]. As with other forms of invasive aspergillosis, A. fumigatus was the most common cause of Aspergillus NVE. This frequency may relate to the fact that A. fumigatus has smaller conidia (2-3 |im), which allow for more efficient inhalation and bypass of the physical barriers of the respiratory system , from which they subsequently gain access to the bloodstream.
Aspergillus NVE most commonly affects the mitral valve and typically produces large vegetations, with the average size being approximately 40 mm . Despite these large persistent endovascular vegetations, blood cultures are usually negative due to the facts that fungemia is intermittent and that Aspergillus spp. almost never grow in convential blood cultures media [418,420]. The sensitivity of blood culture for isolating Aspergillus spp. is 10-30% at most . However, these large vegetations can usually be visualized by echocardiography, with transesophageal echocardiography (TEE) demonstrating higher sensitivity than trans-thoracic modality. Culture of embolic material, usually a cutaneous lesion, is a reliable means of establishing a rapid, presumptive diagnosis. Serologic diagnosis, by detecting host antibody response to the mold, has not proven an effective means of early diagnosis of infection with Aspergillus spp. . One major reason is the fact that humoral immunity appears to play a minor role in providing host protection during invasive aspergillosis, although patients who recover from invasive aspergillosis develop detectable antibodies to Aspergillus spp. . As well, the sensitivity and specificity of tests for detection of antibodies to Aspergillus spp. are low [425,426].
Promising tests for earlier and more reliable dectection of invasive aspergillosis, in general, include antigen detection tests and nucleic acid amplification. Galactomannan (GM) is a polysac-charide cell-wall component that is released by growing hyphae. The most recent test for detection of GM is an enzyme immunsorbent oassay (EIA), which has been shown in multiple studies to be a promising diagnostic tool for IA in neu-tropenic patients with cancer. However, the reported sensitivity and specificity have been variable (57-100%, and 66-100%, respectively) . P-D-glucan is a cell wall component of yeast and filamentous fungi. It has been found to be detectable in the blood in various invasive fungal infections, including those caused by Candida spp., Aspergillus spp., as well as Fusarium spp., Trichosporon spp., and Saccharomyces spp. . The roles of these fungal antigen detection tests in early diagnosis of fungal endocarditis remain to be determined. Of the nucleic acid-based tests, the use of polymerase chain reaction (PCR) for early but robust confirmation of Aspergillus endocarditis is promising.
The optimum management in patients with Aspergillus NVE remains undefined. Most authors recommend a combination of medical and surgical therapy . For medical treatment, in addition to managing the general complications of endocarditis, administration of antifungal therapy is crucial. AmB has traditionally been the mainstay of treatment for Aspergillus infection. However, the optimal dosage, total dose, and length of therapy have not been established. As mentioned previously, the nephrotoxic effect is the most common reason to limit dose or terminate therapy . AmB also penetrates poorly into cardiac vegetations . Nonetheless, based on retrospective data of few patients who survived Aspergillus endocarditis, the recommended total dosage of AmB is 2.5-3.0 g (or 50 mg/kg) . It is important to remember that despite these high doses with a seemingly effective antifungal agent, clinical success is not guaranteed. The liposomal AmB, with its renal-sparing properties, has been used successfully to treat cases of Aspergillus endocarditis [430,431]; in a few cases, surgery was not required [432,433].
Because of the adverse events associated with AmB, other agents with activity against Aspergillus spp. have been used. 5-FC alone had no effect on survival in an experimental rabbit model of A. fumagatus endocarditis, but when used in combination with AmB (deoxycholate), valve sterilization was achieved in 30% of tested animals . The combination has also proved effective in lowering mortality in neutropenic patients with pulmonary aspergillosis who did not receive a bone marrow transplant . There is a paucity of data on this combination in Aspergillus endocarditis. Nonetheless, the adverse events profile of 5-FC necessitates regular monitoring of blood levels of the drug, as well as complete blood cell count and hepatic enzyme profile, to avoid the risk of toxicity.
Itraconazole, an azole with activity against Aspergillus spp., appears more efficacious than monotherapy with AmB in animal models . However, its pharmacology (i.e., variable intestinal absorption, unpredictable drug interactions) has limited its use in primary treatment of Aspergillus endocarditis. It has been used successfully, however, as antifungal prophylaxis against recurrence once primary treatment was completed [431,433].
Voriconazole, a broad-spectrum triazole anti-fungal, is an appropriate agent for therapy for invasive aspergillosis . Superior outcomes were obtained for hematological patients with aspergillosis who were treated with voriconazole, compared with conventional amphotericin B, in a large randomized trial . It is now licensed for treatment of documented aspergillosis and other less common mold infections . Given the superiority of voriconazole over AmB in the above trial, voriconazole could be considered the drug of choice for Aspergillus endocarditis, although no study currently exists to support this suggestion. One case report describes the successful use of oral voriconazole (in conjunction with aggressive surgical debridement) to treat Aspergillus prosthetic valve endocarditis with multiple embolic complications .
Caspofungin is an echinocandin with activity against Aspergillus spp. At this time, there have been no reports on the use of Caspofungin monotherapy for the management of Aspergillus endocarditis.
The optimal duration of antifungal therapy in the acute management of Aspergillus NVE remains undefined, although one study suggests that AmB deoxycholate at 1 mg/kg/day (or lipid-based equivalent) for > 6 weeks is required . This suggestion is based on the fact that embolic episodes with lesions that contain live Aspergillus spp. occurred in patients despite having received up to six weeks of AmB at 1 mg/kg/day. Furthermore, the mortality was high, despite a mean cumulative dose of 27 mg/kg of AmB. In certain cases, combination of AmB with 5-FC should be considered. The optimal duration of azoles in the management of acute disease is undefined, although this point may be moot as these are the agents most likely to be used for suppressive therapy (see below).
Surgery is an important adjunct to medical treatment and is recommended in all cases
[339,418,424,435]. Evidence supporting this suggestion derives from the dismal mortality rates among all patients with Aspergillus endocarditis treated with medical therapy alone (100%) versus the survival rates for those who undergo a combined medical/surgical approach (<20%) . However, one study found that surgical intervention with valve replacement did not improve moratlity rates, when compared with rates for patients who underwent antifungal therapy alone . This discordance may be related to the antifungal therapies available that constitute medical therapy. Radical debride-ment of necrotic tissue with valve replacement using biomaterials (bioprosthesis or homo-grafts) with or without aortic root replacement is the recommended procedure . Lavage of the endocardium with an AmB solution is not efficacious and is no longer considered standard technique .
Despite the use of medical and surgical interventions, recurrence rate can be as high as 40% . This high rate of relapse indicates the need for long-term antifungal maintenance therapy (sometimes referred to as "prophylaxis"), after treatment of the acute episode. Azoles have been used for this purpose, particularly itraconazole. Although voriconazole is not licenced for prophylaxis, a guinea pig model suggests that it is highly efficacious in the prevention and treatment of Aspergillus endocarditis and may be superior to itraconazole . A minimum of two years of maintenance therapy is recommended using itra-conazole, although given the potential disastrous complication of recurrence, lifelong therapy may be advocated for some patients .
Aspergillus mural endocarditis (ME) is a distinct clinical syndrome that differs from valvular endocarditis. Defined as growth or vegetations along the lining of the walls of the cardiac chambers with or without antecedent valvular lesions, it most commonly develops in patients with high levels of immunosuppression, particularly recipients of solid organ transplants [418,423]. ME is highly characteristic of Aspergillus spp. and it has been demonstrated in one-third of patients with Aspergillus endocarditis . ME typically results from de novo seeding of an abnormal area of endocardium, or as a continguous extension of infection from underlying myocardial abscess . On autopsy, it appears as white-yellow-gray excrescences typically several millimeters in diameter . This diagnosis is difficult to confirm, even by echocardiography, although TEE is likely more sensitive [418,423,441]. The major complication associated with Aspergillus ME is embolic phenomena, typically producing micro-emboli leading to metastatic septic foci, rather than large occlusive emboli [423,440]. Fistulous tracts and cardiac rupture may also occur. The optimal management of this condition is poorly defined, but likely a combined medical and surgical approach, as for Aspergillus NVE, may be appropriate [418,442].
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