Answer to Q1

The differential diagnosis should include:

1. Infective endocarditis (IE) – fever, mitral regurgitation, crackles suggestive of pulmonary oedema, indwelling central venous catheter as the possible source of infection
2. Nosocomial catheter-related sepsis – fever, chronic haemodialysis with indwelling central venous catheter as the possible source of infection
3. Community-acquired pneumonia (including tuberculosis) – HIV-infected, fever, pulmonary crackles, underlying diabetes mellitus
4. Fluid overload - crackles suggestive of pulmonary oedema

However, the diagnosis of IE fits best with the clinical history, examination and initial investigations. The aetiological causes of IE are numerous but broadly include bacterial and fungal pathogens. In order to confirm a diagnosis of IE, blood cultures and echocardiography should be performed immediately. Three sets of blood cultures should be obtained, preferably from different venepuncture sites and at different times (spaced at least 30 minutes apart).[1] This allows documentation of a continuous (rather than transient or intermittent) bloodstream infection which improves the specificity of an IE diagnosis. For adults, each blood culture bottle should contain at least 10 ml of blood to increase the yield. Prolonged incubation of blood cultures may be required for detection of fastidious or slow-growing pathogens (several weeks in some cases). In addition, a set of blood cultures obtained through the CVC could provide useful information. To minimise the chance of contamination of blood cultures, it is important to ensure proper skin antisepsis is performed before venepuncture; for blood obtained through the CVC, the port should first be disinfected with 70% alcohol. Other baseline investigations that would provide useful supporting evidence include a chest radiograph, full blood count with differential, C-reactive protein and serum 1,3 β-d glucan assay (this is helpful if a fungal cause of IE is likely because of the low sensitivity of blood cultures). The patient’s renal function would also need to be carefully monitored.

A single set of blood cultures cultured Candida parapsilosis.

The 1,3 β-d glucan levels were also markedly elevated (>523 pg/ml). Based on the pathogen identity and due to his impaired renal function, the patient was empirically started on intravenous fluconazole. On echocardiography, large, friable mitral valve vegetations were observed consistent with a diagnosis of fungal infective endocarditis (Figure 1). Blood cultures submitted 48 hours after commencing fluconazole, cultured the same organism.

Answer to Q3

1,3 β-d glucan, a cell wall component of many fungi, is detected by the Fungitell assay (Associates of Cape Cod Clinical Diagnostics, MA). The assay assists with early diagnosis of fungal bloodstream infections as it is often positive before traditional blood cultures. In one study, the 1,3 β-d glucan assay levels were found to be significantly higher in patients with C. parapsilosis, C. tropicalis and C. guilliermondii IE compared to those with Candida albicans endocarditis.[2]. In a meta-analysis published in 2011, the pooled sensitivity and specificity for diagnosis was 77% and 88% respectively.[3] This assay is also positive in patients with Pneumocystis pneumonia (PCP) but negative in patients with mucormycosis or cryptococcosis. β-D-glucan assay levels may be falsely elevated in patients with bacteraemia and in those on intravenous antibiotics (such as amoxicillin-clavulanic acid), immunoglobulin and haemodialysis where cellulose membranes have been utilized.[4]

The elevated follow-up 1,3 β-d glucan level in this patient was probably not clinically significant:

1. Although the patient is HIV-infected, PCP was ruled out both clinically and radiologically.
2. Dialysis was performed using synthetic polysulfone membranes which do not significantly elevate levels of 1,3 β-d glucan.
3. Elevated levels post-commencement of treatment have been described previously: high levels which are observed during the early phase of the disease do not always return to baseline during the early stages of antifungal therapy.[2, 3]
4. An important consideration in this patient is a persistent nidus of infection as he was treated with a fungistatic agent. However, blood cultures remained negative following surgical removal of the infected valve.

Question 4: What is the long-term management of this patient?