Culture-Negative Infective Endocarditis in the Modern Diagnostic Era: Patient Characteristics and Heterogeneity in a Nationwide Cohort

BACKGROUND: Culture-negative infective endocarditis (CNIE) remains a diagnostic and therapeutic challenge. Current evidence on this disease is limited by small sample sizes, lack of granularity, and highly selected data.

OBJECTIVES: This study sought to provide a granular characterization of CNIE in the modern diagnostic era from the first nationwide cohort of patients with infective endocarditis (IE).

METHODS: This study used data from the nationwide Danish NIDUS (NatIonal Danish endocarditis stUdieS) registry, including all patients hospitalized with first-time left-sided IE (2016-2021). Patients were categorized as having CNIE or culture-positive infective endocarditis (CPIE) on the basis of blood cultures, valve tissue cultures, and polymerase chain reaction analyses. The study described patients' medical history, IE-specific disease features, clinical practice patterns, and treatment regimens.

RESULTS: Of 2,875 IE patients, 212 (7.4%) had CNIE. Compared with CPIE, CNIE patients were more likely to have congenital heart disease (9.9% vs 2.9%) and less likely to have previous cancer (9.3% vs 14.7%). At admission, CNIE patients presented less frequently with sepsis (7.1% vs 24.6%) and fever (44.3% vs 61.7%), but they presented more often with embolism (25.9% vs 10.8%) and valvular insufficiency (11.3% vs 7.4%). The median size of vegetations was smaller (8 mm vs 10 mm) for patients with CNIE, whereas rates of prosthetic valve infection (22.2% vs 23.1%) and valve surgery (20.3% vs 21.8%) were similar. Positron emission tomography with computed tomography (PET-CT) was commonly used in both groups (67%-68%), and it was diagnostic in 13.1% of CNIE cases and 10.7% of CPIE cases. Among patients with prosthetic valve CNIE, the diagnostic yield of PET-CT was almost 50%.

CONCLUSIONS: Using the first nationwide, unselected IE cohort, this study demonstrated a lower proportion of culture-negative cases than reported in previous studies. Patients with CNIE differed from CPIE in clinical presentation and disease characteristics, notably with less frequent fever and sepsis but higher embolic complication rates. However, culture-negative IE is highly heterogeneous and is better defined by distinct subgroups rather than by a single phenotype.