Diagnostic, cardiac imaging, and management considerations in fungal infective endocarditis: a contemporary narrative review

Introduction

Infective endocarditis (IE) represents a considerable global health concern, affects both native and prosthetic tissues, and is commonly associated with serious complications. Fungal IE (FIE) is a relatively rare cause of IE, accounting for a reported 1% of IE cases in the literature (1,2), and thus poses many challenges in both diagnosis and clinical management. Despite its low prevalence compared to bacterial endocarditis, FIE is associated with disproportionately higher morbidity and mortality, with case fatality rates up to 70% (2). Increasing prevalence of both valvular heart disease and subsequent valve replacement therapy in an aging population, as well as rates of immunocompromised status in the setting of systemic oncologic and immunomodulatory therapies, pose a potential risk for increased prevalence of fungal endocarditis (3). In light of this, it is important for clinicians to maintain familiarity with the challenges associated with the diagnosis and treatment of FIE. We present this article in accordance with the Narrative Review reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0091/rc).

Methods

In September 2025, a search of the PubMed database was conducted for English-language articles published between January 2000 and September 2025 related to epidemiology, diagnosis, and treatment of fungal endocarditis. Search terms included combinations of “endocarditis”, “fungal”, “candida”, “aspergillus”, “histoplasma” and “diagnosis”, “imaging”, and “therapy” among others. Publications were screened, and relevant articles were included in this narrative review. Additional searches were performed to locate professional society guidelines and select references pertaining to non-fungal endocarditis. The complete search strategy is outlined in Table 1, and a detailed search strategy is provided in Table S1.

Epidemiology, pathogenesis, and microbiology

FIE represents around 1% of all cases of IE in the literature (2). A prospective study of 2,781 patients with definite endocarditis between 2000 and 2005 found FIE to represent 1% of native valve cases, 4% of prosthetic valve IE, and 2% of other intracardiac device infections (1), though it is worth noting that 10% of patients had persistently negative cultures, so the reported findings may underestimate the actual prevalence of FIE in this cohort. The most common pathogens implicated in FIE are Candida spp. (2), accounting for around 50% of FIE cases (4) and bearing a high mortality rate (30.3% death at discharge in FIE compared to 17% for non-FIE in one European cohort study) (5). In this same study, patients with Candida endocarditis were more likely to have prosthetic valves, short-term indwelling catheters, and nosocomial source of infection compared to IE patients generally (5). Candida spp. possess morphological features such as a hyphal and pseudohyphal form as well as virulence factors such as the production of biofilms in some species, which promote adherence to valvular and endocardial tissue, allow adherence to inorganic prosthetic materials, and enable evasion of immune surveillance (2). Pathogenesis commonly results from fungemia secondary to dissemination across the intestinal epithelium or skin barrier, and is dependent on the yeast’s ability to undergo hyphal transformation (2). Other pathogens in FIE include Aspergillus spp., Histoplasma spp., and Cryptococcus spp. (2,4). Aspergillus endocarditis is the second most common pathogen in FIE, responsible for around 24% of cases (2), and is more common in patients with prior valve replacement as well as solid organ transplant, with continued immunosuppressed status being strongly associated with increased risk of death (6,7). Aspergillus IE has previously been described as affecting mostly males (2); however, one analysis of 61 cases of Aspergillus IE between 2008 and 2019 found that 44.3% of patients were female (6). Histoplasma spp. are a less common cause of endocarditis compared to Candida spp. and Aspergillus spp. (4), but are associated with late diagnosis and poor outcomes (8). In a case series of 14 patients treated for definitive Histoplasma endocarditis between 2003 and 2012 in centers across the United States, diagnosis took an average of 7 weeks from onset of symptoms, and only 6 of 14 (43%) of patients had a positive blood culture (8). Notably, 10 of 14 patients had a prosthetic aortic valve, and all patients were male (8).

Clinical presentation

FIE may present with a variety of symptoms that depend on the cardiac structures involved, degree of extracardiac involvement, and underlying risk factors. Nonspecific systemic symptoms, such as malaise, fatigue, chills, fever, and weight loss, are common (9). Notably, while fever is present in >90% of cases of bacterial endocarditis, fungal endocarditis due to Candida specifically has been shown to be associated with lower rates of fever at presentation (60–70%) (9,10). Though clinical presentation varies immensely, common findings in the literature include a changing or new heart murmur, major peripheral embolization, focal or generalized neurological features, heart failure, and dyspnea (4,9).

Diagnosis

Diagnosis of FIE is made on the basis of the modified Duke criteria and 2023 Duke-International Society for Cardiovascular Infectious Diseases (ISCVID) criteria (Figure 1), which include positive blood cultures, laboratory tests (Table 2), and imaging findings (11). While blood culture remains the standard for diagnosing IE, slow growth and the need for specific growth media in the case of fungi may result in negative blood cultures. Though fungi like Candida spp. can be identified using blood culture or polymerase chain reaction (PCR) and antigen testing, the existence of various strains that produce less-tested substrates, as well as the possibility of infection by other, slower-growing fungi, pose considerable obstacles to timely laboratory diagnosis (9). For example, in a case series of 14 patients with Histoplasma endocarditis, blood cultures failed to grow Histoplasma in 57% of patients; however, Histoplasma antigen was detected in blood or urine of 79% of patients, and antibody testing was positive in 6 of 8 patients (75%) (8). Another review of 60 patients with Histoplasma endocarditis between 1940 and 2020 found that blood cultures were positive for Histoplasma capsulatum in 2/13 (15.4%) of native valve endocarditis cases and 5/10 (50%) of prosthetic valve endocarditis cases (12).

Figure 1 Diagnostic and treatment algorithm in suspected fungal endocarditis. ¹⁸F-FDG PET, 18-fluorine fluorodeoxyglucose positron emission tomography; CIED, cardiac implantable electronic device; CT, computed tomography; HF, heart failure; IE, infective endocarditis; IV, intravenous; IVDU, intravenous drug use; oHCM, obstructive hypertrophic cardiomyopathy; PE, pulmonary embolism; TEE, transesophageal echocardiogram.

The use of the 1,3-β-D-glucan (BDG) and mannan/anti-mannan antibody assays, as well as galactomannan (GM) assays, may provide more timely confirmation of invasive fungal infection due to Candida and Aspergillus, respectively (9,13), though a large analysis of the utility of these methods in FIE specifically has yet to be performed. One 2012 retrospective study of 30 Candida endocarditis patients found that mannan or anti-mannan antibodies were detected in 16 out of 18 tested patients (80%) and 1,3-BDG was positive in 18 out of 18 patients (100%), highlighting the usefulness of serum markers in assisting diagnosis (14). Though expeditious, it is worth noting that 1,3-BGD and GM assays are limited by a high rate of false positives related to β-lactam antibiotics, transfusions, and concomitant bacterial infections; thus, patient comorbidities must be taken into account when interpreting findings of these assays (15). As such, the 2023 Duke-ISCVID criteria currently do not include these assays as major criteria for diagnosing FIE (11). In light of these limitations, molecular diagnostic methods are becoming increasingly useful as part of a multimodal diagnostic approach. In particular, cell-free DNA (cfDNA) sequencing has emerged as a useful adjunct to standard testing in suspected IE, though data suggest these tests may be most useful when pre-test probability is quite high due to a high rate of false positives (16). One retrospective study of 506 patients with definitive invasive fungal infection found 88.5% concordance between serum-derived cfDNA PCR and subsequent tissue specimen or bronchoalveolar lavage results, suggesting the utility of cfDNA in earlier stages of the diagnostic process (17). Additionally, PCR has been shown to be both highly sensitive and specific in detecting invasive candidiasis (18), though no large study has been performed in fungal endocarditis specifically. In the aforementioned 30-patient retrospective study, 4 out of 6 patients with Candida endocarditis who had serum PCR testing had positive results, while the remaining 2 patients had uninterpretable results due to superimposed DNA sequences (14).

Echocardiography remains the first-line imaging modality in identifying potential FIE (Table 3). Transthoracic echocardiography (TTE), due to its wide availability, is commonly used in suspected endocarditis (19). However, visualization of all valves and particularly prosthetic valves and implanted devices is better achieved using transesophageal echocardiography (TEE) (20). Negative TTE with persistent clinical findings warrants TEE: a 2017 meta-analysis comparing TTE to TEE in suspected IE found that TTE had a negative likelihood ratio of 0.42 overall and as low as 0.14 in conclusively negative TTEs when patients with prosthetic valves were excluded (21). In other words, a conclusively negative TTE in a patient without a prosthetic valve may be sufficient in ruling out IE, whereas in patients with prosthetic valves, TEE is most likely required even if TTE is negative (21). Similarly, a contemporary cohort study of 82 patients with FIE between 2009 and 2021 showed that vegetations were identified by TTE in 64% of studies compared to 82% of studies using TEE (22). In this cohort, FIE was characterized by large vegetations (1.7±0.8 cm on TTE vs. 1.8±0.9 cm). Vegetations were often mobile (65% of cases on TTE vs. 78% on TEE) and associated with valvular thickening (51% of cases on TTE vs. 61% on TEE) (22). The large and mobile nature of FIE vegetations highlights both the value of cardiac imaging for diagnosis as well as the need for earlier diagnosis and treatment due to high embolic risk (9). TEE is additionally superior to TTE in identifying smaller vegetations, perivalvular abscesses, and pseudoaneurysms (23), and improvements in ultrasound imaging probes providing higher frame rates and image resolution as well as three-dimensional (3D) imaging have demonstrated improved diagnostic performance for endocarditis, particularly for prosthetic valve IE (24). The added sensitivity of TEE for paravalvular complications warrants the use of both TTE and TEE during initial evaluation to detect paravalvular complications, which is reflected in the updated European Society of Cardiology (ESC) guidelines (25-27). Furthermore, specific appearance of vegetations on echocardiography may trigger suspicion of fungal etiology: in a 2001 review of 12 patients with Candida IE, 11/12 patient echocardiograms were described as showing “large dense heterogenous” vegetations (28). This may increase suspicion of Candida IE, as bacterial vegetations often present as pedunculated masses with similar density to native tissue. Conversely, vegetations of Aspergillus spp. are often large and pedunculated, further highlighting the role of echocardiography in guiding further diagnostics and treatment without providing certainty about causal organisms (29). Echocardiography has also shown utility as a screening tool in patients with known fungemia. A 2015 prospective cohort study in which 187 patients with known candidemia underwent TTE or TEE detected Candida endocarditis in 11 patients, 3 of which presented with no signs raising clinical suspicion of endocarditis (30). This finding further supports the use of echocardiography early in the workup of suspected FIE.

In the scenario of inconclusive imaging findings or contraindications to TEE, cardiac computed tomography (CT) could be considered as an adjuvant imaging modality. Cardiac CT has comparable sensitivity for detecting IE as TEE, especially in the setting of prosthetic valves (31). Cardiac CT has additional value in detecting aortic root involvement in aortic valve endocarditis, enabling coronary evaluation perioperatively, and overcoming challenges related to poor ultrasound imaging windows such as in the setting of emphysema and morbid obesity (31,32). Tachycardia and irregular heart rhythms limit the utility of this modality, as gated CT is needed to visualize cardiac structures in a state of minimal motion (32). In the aforementioned contemporary study of FIE, CT was performed in 54 of 82 patients, which detected additional cases of aortic graft involvement (n=2), paravalvular abscess (n=5), and fistula (n=1). Extracardiac involvement by CT included pulmonary septic emboli (n=11), splenic infarcts (n=3), and mediastinal fistulas (n=4) (22). As such, CT provides information essential to surgical planning.

18-Fluorine fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) and white blood cell single-photon emission CT (WBC SPECT) scintigraphy rely on uptake of radiolabeled material to localize metabolically hyperactive tissue and inflammation, respectively. ¹⁸F-FDG PET has now been incorporated as part of the updated 2023 Duke-ISCVID criteria for IE (11), and has been recommended for patients with suspected prosthetic valve IE in the major guidelines (27,33,34). One study found that the inclusion of ¹⁸F-FDG PET imaging increased the sensitivity of the Duke criteria at admission from 70% to 97% in a cohort of 72 patients (35). In the case of invasive fungal infections, ¹⁸F-FDG PET was shown to add value in clinical decision-making in 74% of cases by providing additional information that influenced the decision to discontinue, prolong, or modify antifungal therapy (36). Additional studies regarding the use of ¹⁸F-FDG PET and WBC SPECT in identification of infective valvular changes in FIE specifically are needed. Of note, 4 patients in the aforementioned contemporary study of FIE underwent nuclear imaging (3 ¹⁸F-FDG PET and 1 leukocyte scintigraphy), and in all cases nuclear imaging failed to demonstrate intracardiac uptake (22). In a retrospective study of 14 Candida endocarditis cases between 2012 and 2019 in which 5/14 patients had prosthetic valve endocarditis, ¹⁸F-FDG PET was found to have a sensitivity of 57.1%, compared to 54.5% sensitivity for TTE performed in the same cohort, though the authors note that pre-test dietary preparation was not consistently performed, which may limit the usefulness of these findings (37). Until larger studies are conducted, it is plausible that nuclear imaging modalities including ¹⁸F-FDG PET imaging may have reduced diagnostic sensitivity for native valvular changes in FIE, in comparison to bacterial IE. To this end, the American Society of Nuclear Cardiology Imaging Indications (ASNC-I²) has labeled WBC SPECT “Rarely Appropriate” in native valve endocarditis due to its low sensitivity in the diagnosis of fungal infections, though it notes that the use of high-sensitivity SPECT/CT cameras may improve performance (38). Nuclear imaging has several limitations, namely decreased sensitivity in native valve endocarditis compared to prosthetic valve endocarditis (39), as well as a high rate of false positives within the first several months following surgery, as healing tissue exhibits higher uptake (32). The ASNC-I² Consensus Recommendations specify that in native valve FIE, ¹⁸F-FDG PET “May Be Appropriate” whereas WBC SPECT is “Rarely Appropriate”; in the case of prosthetic valve FIE, both modalities are “Strongly Recommended” in the event of negative echocardiography and strong clinical suspicion, with ¹⁸F-FDG PET being preferred due to a lower rate of false negatives than WBC SPECT (38). Magnetic resonance imaging (MRI) has utility primarily in the form of cerebral MRI, which is indicated in patients with neurologic impairment in the setting of known or suspected endocarditis, or in asymptomatic patients perioperatively to assess intracranial bleeding risk due to mycotic aneurysm (11). Cardiac MRI has at present not been shown to be superior to echocardiography as a diagnostic tool in IE, and should not be utilized as a primary imaging modality for FIE.

Treatment of FIE

Since FIE makes up a relatively small proportion of IE cases, evidence for treatment strategies is largely based on observational studies. The 2020 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline for the Management of Patients with Valvular Heart Disease describes FIE as an indication for early surgical replacement of an infected valve, and recommends a combination of surgery and an amphotericin B-containing product as the initial treatment for most cases. In the case of Candida endocarditis, the recommended regimen is lipid amphotericin B (3 to 5 mg/kg per day) with the possible addition of 25 mg/kg flucytosine four times daily (40,41), or high-dose echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) (41). Of note, a multi-national prospective cohort study of 70 patients with Candida endocarditis found no difference in mortality between patients treated with amphotericin B and echinocandins, suggesting that initial antifungal therapy may be effectively tailored to patients with regards to renal and hepatic comorbidities, for example (42). Interestingly, this same cohort study found no difference in mortality for patients receiving adjunctive surgery compared to antifungal therapy alone, despite the fact that patients receiving surgery were younger (42). For Aspergillus, voriconazole and lipid amphotericin B are both suggested as first-line options (29). While there is no standard approach to management of Histoplasma endocarditis suggested by a major medical society, one review of cases found lipid amphotericin B at 5 mg/kg per day for 4–6 weeks, followed by oral itraconazole or other azole for at least 12 months to be a common approach (8). Similarly, in the case of Histoplasma, the European Confederation of Medical Mycology and International Society for Human and Animal Mycology cryptococcosis guideline recommends treating non-pulmonary, non-CNS cryptococcemia and disseminated disease using the same regimen as for CNS disease, which lipid amphotericin B 3–4 mg/kg daily plus 5-flucytosine 25 mg/kg four times a day for 2 weeks [with prolongation if cerebrospinal fluid (CSF) culture is positive at 2 weeks] followed by fluconazole 400–800 mg daily for 8 weeks (43).

Given the number of culture-negative cases, especially those caused by fungi like Aspergillus, the choice of fungicidal therapy is often guided by surgical pathology and culture of specimens. Initial antifungal therapy is given for at least 6 weeks, and suppressive therapy with oral azoles is often included thereafter (40). Valve replacement is recommended in definitive Candida endocarditis both in prosthetic and native valve infections (41). For cardiac implantable electronic device (CIED) infections, the entire device and leads should be removed (5). Similarly, surgery is recommended in the case of Aspergillus endocarditis (29). While standard recommendations guiding surgery do not exist for the less common pathogens, the majority of patients with endocarditis caused by other fungi in the previously discussed case series and retrospective studies underwent adjuvant surgery (8,12,42). Due to the frequently large and mobile nature of fungal vegetations, surgery may often be indicated on the basis of vegetation size as well as native or prosthetic valve dysfunction (26). Analysis of the previously mentioned 82-patient cohort showed a survival benefit to combined surgical and medical therapy compared to medical therapy alone, though selection bias related to surgical candidacy limits the saliency of these data (22). The aforementioned case series of 14 patients with Histoplasma endocarditis showed that 11 of 14 patients underwent adjuvant surgery, and 11 of 14 patients received lipid amphotericin B for a median of 29 days, with 9 patients receiving oral itraconazole long term, ranging from 6 months to lifelong therapy (8). Of note, of all 3 patients who died had received either minimal or no amphotericin B treatment (8). One 879-case meta-analysis of Candida IE cases showed a reduction of death [prevalence odds ratio, 0.56; 95% confidence interval (CI): 0.16–1.99] in patients receiving combined antifungal therapy and valve surgery (44). In patients with CIED-related endocarditis or following valve replacement, it is important to note that new prosthetic material poses a risk factor for recurrent FIE, which highlights the importance of including long-term azole therapy in these cases (2). It is important to note that current recommendations are based on expert opinion and retrospective cohort studies rather than randomized clinical trial data, and surveillance using the aforementioned imaging modalities provides the opportunity to judiciously modify treatment when warranted.

Discussion

Our review highlights the difficulties associated with diagnosing FIE, as well as the difficulties that emerge in treatment in light of the high mortality rates, numerous causal organisms, as well as lack of large clinical trials to inform the optimal choice of therapy. Though FIE is largely (>50%) a disease caused by Candida spp., endocarditis caused by other fungi, including Aspergillus spp. and Histoplasma spp. makes up a considerable proportion of FIE cases. Our review is limited by the exclusion of individual case reports and non-English publications, as it is likely that more data exist in these forms than in larger datasets for FIE specifically when compared to more common causes of IE. While much of the currently available data is limited by relatively small sample sizes, as more large centers assemble retrospective data on FIE, we hope that larger and multicenter analyses will enable a clearer view of optimal management strategies, particularly with regards to the utility of newer antifungal agents. We also hope that such data will reveal helpful trends regarding modifiable factors associated with improved long-term outcomes, as long-term survival continues to be poor despite improvement in recent years (4,22,45).

Conclusions

FIE continues to be a condition associated with high mortality and poor outcomes. Increasing prevalence of immunocompromised status and increasing prevalence of prosthetic valve apparatus pose important risk factors for clinicians to be aware of, with the latter being a particularly common finding in FIE patients in the literature. Cardiac imaging, particularly echocardiography, remains a cornerstone for timely diagnosis and guidance of treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0091/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0091/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0091/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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