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 Table of Contents  
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 27-30

Culture-negative fungal endocarditis

Department of Medicine, AIIMS, New Delhi, India

Date of Submission15-Aug-2019
Date of Acceptance25-Sep-2019
Date of Web Publication12-Nov-2019

Correspondence Address:
Dr. Prabhat Kumar
Department of Medicine, AIIMS, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/hm.hm_31_19

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A 54-year-old female, known case of hypertension and diabetes mellitus (controlled), was admitted with prolonged fever for 1½ months. On evaluation, fever workup was inconclusive and multiple cultures were negative. On re-assessment of history, she gave a history of cardiac catheterization 1 month back. Further evaluation revealed aortic valve vegetation on two-dimensional echo with raised beta-D glucan levels. She was managed with antifungal therapy followed by valve replacement surgery. The patient improved following the management and is doing fine. This case highlights the importance of detailed history-taking and evaluation. It also highlights the not uncommon occurrence of fungal endocarditis in patients with healthcare contact and the role of biomarkers as surrogate in case of culture-negative endocarditis.

Keywords: Biomarkers, caspofungin, endocarditis

How to cite this article:
Kumar R, Kirtana J, Kodan P, Ray Y, Kumar P, Biswas A. Culture-negative fungal endocarditis. Heart Mind 2019;3:27-30

How to cite this URL:
Kumar R, Kirtana J, Kodan P, Ray Y, Kumar P, Biswas A. Culture-negative fungal endocarditis. Heart Mind [serial online] 2019 [cited 2023 Mar 27];3:27-30. Available from: http://www.heartmindjournal.org/text.asp?2019/3/1/27/270769

  Introduction Top

Infective endocarditis (IE) is characterized by the formation of vegetation (infective foci) on the valvular cusps. The disease process may involve healthy as well as diseased tissue depending upon the virulence of the microorganism. Diagnosis is established by the demonstration of endocardium involvement (vegetations) along with the identification of the organism in the tissue cultures (infected valves) or blood cultures. Since IE is a state of sepsis, it often compels a physician to start antibiotics empirically even without confirming the diagnosis of IE. This results in lack of enough blood sample collection for cultures. Furthermore, transthoracic echocardiography (TTE) is less sensitive in case of smaller vegetation. Culture-negative endocarditis (CNE) includes cases where etiological organism remains unidentified. CNE contributes to about 5%–10% (as high as 20%) of all IE cases.[1] While previous exposure to antibiotics is the most common reason, it may be due to several other reasons. Apart from this, IE due to fastidious organisms or organism requiring special culture techniques or specimen processing contributes significantly to CNE. It is pertinent to obtain a detailed antimicrobial history as well as detailed personal history (including travel history, animal contact, healthcare contact, and devices or implants) to identify risk factors predisposing to these organisms and to guide the therapy in such cases.

Fungal endocarditis is uncommon but contributes significantly to mortality and morbidity due to associated complications. It gains special consideration in case of intravenous drug users, immunocompromised status, previous healthcare contact, intravascular devices, and prolonged antibiotics use due to related or unrelated indications.[1] In case of CNE due to suspected fungal causes (most common – Aspergillus spp. and Candida spp.), biomarkers may be used as surrogate for diagnosis and follow-up.[2] This case highlights the importance of detailed history-taking and the use of noninvasive biomarkers in case of CNE. We also describe the approach to a case of CNE.

  Case Report Top

A 54-year-old female, known case of hypertension and diabetes mellitus for 1 year, was admitted with complaints of fever for 1½ months' along with abdominal pain for 4 days and shortness of breath with pedal edema for 3 days.

She was apparently fine 1½ months back when she developed fever (101°F–102°F), on and off, which was relieved by antipyretics. There was no periodicity or diurnal variation. There were no systemic localizing features. There was no history of recent travel or animal contact. As the fever continued despite taking medications, including antibiotics (records not available) and nothing suggestive on routine investigations, she was admitted in a private hospital for evaluation and management of the same. Initial evaluation including cultures, urine examinations, autoimmune markers, and imaging was negative. Further, two-dimensional (2D) echo was done which revealed vegetation measuring around 6 mm on the aortic valve. She was started on intravenous antibiotics (ceftriaxone and vancomycin) in view of suspected bacterial endocarditis. She continued to have high-grade fever despite 3 weeks of antibiotic therapy. She also had complaints of acute-onset abdominal pain, localized over the left upper quadrant for 4 days, with no features suggestive of intestinal obstruction and no urinary or bowel disturbance. There was history of worsening of shortness of breath along with orthopnea and bilateral lower limb swelling for 3 days. In view of IE with persistent fever and new complaints, she was referred to our hospital.

On examination, Glasgow coma scale – full, pulse rate – 114/min, regular with all peripheral pulses palpable, blood pressure – 110/68 mmHg, respiratory rate – 24/min; pallor and pitting-type edema in the dependent areas was noted in general examination. Further, systemic examination revealed bilateral basal crepitations and soft S1 with low pitched early diastolic murmur; other systemic examination was unremarkable. Initial investigations revealed anemia, mild thrombocytopenia with normal total leukocyte count, deranged kidney function test, and raised erythrocyte sedimentation rate and C-reactive protein with negative autoimmune markers. There was microscopic hematuria and mild proteinuria on urine examination along with raised serum NT-proBNP levels [Table 1]. Ultrasound abdomen revealed splenic infarct (likely embolic phenomenon) as the cause of abdominal pain. She was continued on intravenous antibiotics (meropenem and teicoplanin), along with fluid restriction and carefully monitored diuretics, suspecting partially treated endocarditis. She underwent a repeat TTE which revealed large oscillating vegetation (around 13 mm) on the aortic valve along with moderate regurgitation. Blood investigations were inconclusive along with negative culture reports. As she continued to have fever, considering CNE, history was re-assessed for possible risk factors and related etiologies. A significantly important history of healthcare contact was obtained, i.e., she underwent cardiac catheterization 1 month before onset of fever for chest pain (coronary angiography, which was normal). Considering nosocomial organisms as possible causes, repeat blood samples were sent for bacteriological as well as fungal cultures along with serum galactomannan and beta-D-glucan. Noninfective causes of CNE were ruled out using appropriate investigations. Repeat cultures were negative with low galactomannan but raised beta-D-glucan levels [Table 1]. She was started on intravenous caspofungin considering fungal endocarditis in view of negative cultures, raised beta-D-glucan levels, and large vegetation, following which she became afebrile after 6 days. She underwent aortic valve replacement indicated because of large vegetation on aortic valve, suspicion of fungal endocarditis, and features of heart failure refractory to medical therapy alone. Intraoperatively, thick and calcified aortic valve cusps were noted along with an 11 mm × 6 mm vegetation of the left coronary cusp; excised tissue was sent for cultures, which were all negative. However, the patient improved clinically and symptomatically. She was discharged on oral fluconazole with a plan to continue for at least 6 weeks postoperatively. At the time of submission, the patient was doing fine and was following regularly in the cardiothoracic and vascular surgery outpatient department and Infectious disease ID clinic.
Table 1: Investigations chart

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  Discussion Top

IE is a serious and life-threatening cardiovascular infection. It is caused by microorganisms of all sorts and of variable virulence, which may affect native (healthy as well as disease tissue) or prosthetic surfaces. Diagnosis is established by identifying the organism from the diseased tissue itself, which necessitates invasive approach. A clinical criterion, i.e., modified Duke's criteria, has been proposed for the diagnosis of IE as an alternative, in cases where surgical specimen is not feasible.[1],[3] IE is characterized by persistent bacteremia; therefore, criteria require majority of the blood cultures to be positive in an appropriate setting as a major criterion to attribute it as a cause of IE. Empirical therapy of IE is guided by risk factors and predisposing condition whereas definitive therapy is guided by cultures. The situation is further complicated by negative cultures where etiological organisms remain unidentified. CNE contributes to about 10%–15% of total cases. The situation of CNE arises due to previous antimicrobial exposure (true bacterial endocarditis where culture are negative due to antimicrobial use); infectious due to fastidious organisms or those requiring special processing techniques; or by intracellular pathogens where diagnosis is established by serology or molecular methods [4] [Table 2]. Empirical therapy, in such cases, is guided by risk factors and predisposing conditions [Table 2]. Our patient was diagnosed with native aortic valve endocarditis (AOE) on initial 2D echo evaluation (in the absence of traditional risk factors for IE). Aortic valve vegetation may be misinterpreted on 2D echo due to atypical features of vegetation, and therefore, in clinically suspected case, negative echocardiography does not rule out IE.[5],[6] AOE is not an uncommon phenomenon; however, it occurs more commonly in patients with abnormal native valves, e.g., bicuspid aortic valves.[7],[8] Furthermore, AOE is associated with more hemodynamic compromise than in any other valve involvement.[9] Further, cardiac computed tomography (CT) may be of adjunctive benefit in AOE because of diagnostic accuracy similar to transesophageal echocardiography for the detection of local complications (such as paravalvular abscess); CT may also help to characterize aortic valve size, anatomy, calcification of aortic root, as well as coronary status in cases with anticipated surgery.[3] As multiple cultures were negative in this case, the possibility of CNE due to prior antimicrobial use or due to fastidious organisms was considered. Further, revision of history yielded information about previous hospitalization and cardiac catheterization, leading to heightened suspicion of IE due to multidrug resistance pathogens or fungal pathogens. Noninfective causes such as systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APLA) must be ruled out using serological investigations.
Table 2: Culture-negative endocarditis - causative organisms, epidemiological factors

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Fungal endocarditis is an uncommon and fatal cause of IE, constituting about <2% cases of IE. Invasive fungal infections (or candidiasis) usually arise in certain clinical settings, such as neutropenic hosts, immunocompromised state, injection drug use, intravascular devices, and indwelling catheters.[10] Candida spp. and Aspergillus spp. are the most common organisms implicated in fungal IE. While diagnosis is established by positive blood cultures in appropriate clinical settings, some cases present as CNE. In such cases, specific serological tests may be useful depending upon the risk factors. However, the use of biomarkers in CNE is controversial which is supported mainly by anecdotal reports and small studies. A study, where the role of serum galactomannan and mannan antibodies and polymerase chain reaction (PCR) in diagnosis of Aspergillus endocarditis was evaluated, has shown sensitivity and specificity of around 80%.[2] Further, the results of an another study were re-analyzed, evaluating role of biomarkers (beta-D-glucan, PCR) in Candida endocarditis; beta-D-glucan was found to be 100% sensitive with high negative predictive value.[11] As, in this case, she continued to have fever despite appropriate broad-spectrum antibiotics and repeated negative cultures, relevant biomarkers were evaluated; beta-D-glucan levels were found to be elevated and diagnosis of fungal (Candida spp.) endocarditis was established. Management of fungal endocarditis includes antifungal therapy along with valve replacement; she was managed accordingly. Tissue obtained intraoperatively was sent for bacterial, fungal, and tuberculosis cultures, which were sterile possibly due to use of antibiotics and antifungal agents.

In case of blood CNE, empirically therapy is guided by epidemiology, risk factors, and symptomatology, i.e.,native valve endocarditis versus prosthetic valve endocarditis (PVE); early versus late PVE; and additional risk factors (region, animal contact, and injection drug use). Causes, risk factors, and relevant investigations for possible organisms are outlined in [Figure 1] and [Table 2].[4],[12] Further therapy needs to be narrowed down on the basis of serology or molecular results as recommended in the American as well as European guidelines.[1],[3] Finally, noninfective causes such as SLE or APLA should be included in diagnostic workup for CNE wherever indicated.
Figure 1: Culture-negative endocarditis – organism profile in different settings (original)

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  Conclusion Top

IE is a life-threatening condition; therefore, high index of suspicion must be kept in appropriate clinical settings. It is important to send multiple blood cultures before initiation of antimicrobials to avoid negative cultures. Fungal endocarditis should be considered a possibility in CNE (even in the absence of traditional risk factors) when no response to appropriate antibiotics. In cases of CNE, biomarkers should be used as a surrogate to establish the diagnosis and to guide the therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr., Tleyjeh IM, Rybak MJ, et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications: A Scientific statement for healthcare professionals from the American Heart Association. Circulation 2015;132:1435-86.  Back to cited text no. 1
Evaluation of Noninvasive Methods for the Diagnosis of Fungal Endocarditis | Medical Mycology | Oxford Academic. Available from: https://academic.oup.com/mmy/article/52/5/530/2802508. [Last accessed on 2019 Aug 13].  Back to cited text no. 2
Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, et al. 2015 ESC guidelines for the management of infective endocarditis: The task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36:3075-128.  Back to cited text no. 3
Ebato M. Blood Culture-Negative Endocarditis. Advanced Concepts in Endocarditis; 12 September, 2018. Available from: https://www.intechopen.com/books/advanced-concepts-in-endocarditis/blood-culture-negative-endocarditis. [Last accessed on 2019 Aug 14].  Back to cited text no. 4
Wray TM. The variable echocardiographic features in aortic valve endocarditis. Circulation 1975;52:658-63.  Back to cited text no. 5
Hirschfeld DS, Schiller N. Localization of aortic valve vegetations by echocardiography. Circulation 1976;53:280-5.  Back to cited text no. 6
Kiyota Y, Della Corte A, Montiero Vieira V, Habchi K, Huang CC, Della Ratta EE, et al. Risk and outcomes of aortic valve endocarditis among patients with bicuspid and tricuspid aortic valves. Open Heart 2017;4:e000545.  Back to cited text no. 7
Van Vlasselaer A, Rasmussen M, Nilsson J, Olaison L, Ragnarsson S. Native aortic versus mitral valve infective endocarditis: A nationwide registry study. Open Heart 2019;6:e000926.  Back to cited text no. 8
Gomes A, Jainandunsing JS, van Assen S, van Geel PP, Sinha B, Gelsomino S, et al. A standardized approach to treat complex aortic valve endocarditis: A case series. J Cardiothorac Surg 2018;13:32.  Back to cited text no. 9
Tattevin P, Revest M, Lefort A, Michelet C, Lortholary O. Fungal endocarditis: Current challenges. Int J Antimicrob Agents 2014;44:290-4.  Back to cited text no. 10
Diagnosis, Management and Outcome of Candida Endocarditis | Elsevier Enhanced Reader. Available from: https://reader.elsevier.com/reader/sd/pii/S1198743X1461466X?token=0115D2876DAD20E51C31990F375 931B012D25AF297F21175335660261C62F1D59F96C13B029C2C2 CE60D4D7229203C68. [Last accessed on 2019 Aug 14].  Back to cited text no. 11
Culture Negative Endocarditis: Advances in Diagnosis and Treatment|IntechOpen. Available from: https://www.intechopen.com/books/contemporary-challenges-in-endocarditis/culture-negative-endocarditis-advances-in-diagnosis-and-treatment. [Last accessed on 2019 Aug 14].  Back to cited text no. 12


  [Figure 1]

  [Table 1], [Table 2]


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