Blood Culture-negative Endocarditis Research Articles

Bartonella endocarditis: lessons learnt from an African cohort

Abstract Background Bartonella (B) quintana endocarditis is a preventable, vector-borne, and important cause of blood culture-negative endocarditis (BCNE). The ESC guideline for the management of endocarditis recommends blood serology (IgG titer ≥800) and polymerase chain reaction (PCR) testing on both blood and valvular tissue for diagnosis. Access to these molecular technologies is limited in Africa and there is a paucity of B. quintana endocarditis research on the continent. Purpose Record the clinical picture and explore the risk factors for disease and the diagnostic utility of immunofluorescence (IFA) in PCR-proven cases with B. quintana endocarditis. Methods Data were analysed from a prospective observational cohort study of patients with infective endocarditis managed at our institution. All BCNE cases from October 2019 to January 2024 were evaluated to identify patients with PCR-proven B. quintana on valvular tissue. A commercially available IFA was used for blood serology testing. 16S rRNA PCR testing with sequencing was performed on valvular tissue. Results Thirty five of the 58 cases (60.3%) with BCNE were diagnosed with Bartonella endocarditis. A diagnosis of PCR-proven B. quintana endocarditis was made in 21 cases. Of these, seven patients (33.3%) were either homeless or lived in informal housing. Thirteen patients (61.9%) had an alcohol-use disorder. Four patients (19%) were Human Immunodeficiency (HIV) virus- positive. Eighteen patients (85.7%) reported the onset of symptoms more than two weeks before presentation. Common presenting symptoms were dyspnea (n=21;100%), loss of weight (n=10;47.6%) and fever (n=7;33.3%). Common clinical features were digital clubbing (n=17;80.9%), pallor (n=13; 61.9%), microscopic haematuria (n=12; 57.1%) and severe regurgitant lesions (n=21; 100%). Blood serology was available in 17 patients with an IgG titer (1≥256) in all patients apart from one (1:64). Only one case (5.8%) had an IgG titre ≥800. The most common isolated valve lesion on echocardiography was severe aortic regurgitation (n=10;47.6%). Surgical replacement and repair were performed in 17(80.9%) and 4(19%) patients respectively. The one-, three- and six-month mortality was 14%, 14 % and 14% respectively. No cases of relapse were reported. Discussion B.quintana is the most prevalent cause of BCNE in our centre. The typical clinical and echocardiographic profile was consistent with the reported literature of a destructive endocarditis in a patient with a low socioeconomic background. Despite this, the surgical outcome is fair and comparable to European data. The IFA used in this study is different to the assay referenced in the ESC guideline and may explain the relatively low serology titres observed (despite PCR-proven disease). Further study with the commercial IFA is needed to determine a cut-off titre that will give a comparable sensitivity to the referenced in-house IFA.Destructive aortic valve endocarditisResultant severe aortic regurgitation

An epidemiological update on infective endocarditis: a two-decade retrospective longitudinal analysis

Abstract Background Infective endocarditis (IE) is a rare yet serious condition affecting the heart valves and the endocardium. Despite advances in management, IE's incidence is on the rise, maintaining a mortality rate similar to that of the late 20th century. Notably, there has been a notable shift in the risk-factor profile, transitioning from traditional factors such as rheumatic heart disease and poor dental health to more iatrogenic causes such as prosthetic heart valves, cardiac devices, foreign body implants, haemodialysis, and immunosuppression. This shift impacts microbiological and imaging diagnosis. Purpose While IE has been extensively studied in the past, the evolving landscape prompts an epidemiological re-evaluation of vulnerable patient populations and the challenges in current diagnostic parameters. Our primary objective is to examine the trends in microbiological and imaging diagnostics over two decades and to compare them across native valve endocarditis (NVE), prosthetic valve endocarditis (PVE), and cardiac implantable electronic device-related IE (CIED-IE). Methods We conducted a retrospective analysis of longitudinal data encompassing 912 patients admitted with either a possible or definite IE diagnosis between 2001 and 2023. Results The incidence of IE increased over the study duration (p<0.01) with octogenarians most affected (21%). Iatrogenic risk factors were associated with nearly two-thirds (63%) of patients diagnosed with IE, while traditional risk factors were evident in almost one-eighth (13%). Blood culture-negative endocarditis increased over the study duration (81% versus73%, p<0.01) and Staphylococcus aureus (29%, p<0.01) became the dominant pathogen over Viridans Streptococcus (14%, p=0.001). Imaging with transthoracic (56% in 2004 versus 75% in 2023) and transoesophageal echocardiography (57% in 2004 versus 79% in 2023) had an increasing contribution in the diagnosis of IE over the two decades. The subgroup analysis found PVE and CIED-IE were more likely to have negative blood cultures (OR=3.7, CI [1.2-6.8] & OR=4.9, CI [1.3-8]) compared to NVE (OR=0.04, CI [0.02-0.8]). PVE and CIED-IE were more likely to have inconclusive imaging (OR=3.7, CI [1.2-6.6] & OR=2.2, CI [0.07-7.8]) compared to NVE (OR=0.63, CI [0.3-3.2]). Complications of stroke were higher in PVE (OR=3.5, CI [0.89-10]) compared to NVE which also had a lower stroke rate (OR=.16, CI [.04-.73]). PVE had more valvular insufficiency (OR=2.1, CI [0.6-4]) compared to NVE (OR=1.2, CI [0.9-6]). The 12-month mortality was no different across the entities (OR=0.3, CI [0.5-7.7] & OR=.49, CI [0.14-1.8] & OR=0.85, CI [0.3-2.4]). Conclusion Our study underscores the evolving nature of IE, now predominantly a healthcare-related disease. Diagnostic challenges persist due to the heterogeneity of the disease, with the emergence of distinct entities such as PVE and CIED-IE.Graphs: Blood culture & echocardiographyForest plot: NVE vs PVE vs CIED-IE

A rare complication of blood culture-negative infective endocarditis (BCNIE) on tricuspid valve: case report

Abstract Background Endocarditis is an infectious disease, with an incidence of about 15 cases per 100.000 people, affecting the tricuspid valve in 10% of cases. Infective endocarditis with negative blood cultures (BCNIE) accounts for more than 20% of cases of infective endocarditis. Perivalvular extension of the infection represents the most detrimental complications of BCNIE. Case Summary A 25-year-old South Asian male was admitted due to fever for 15 days and new onset chest pain. The blood tests showed an increase in inflammatory indices. A chest X-ray showed enlargement of the cardiac shadow. On cardiac examination, a holosystolic murmur at the left sternal edge border was heard. The transthoracic echocardiogram showed a filamentous formation on the tricuspid valve and communication between the aorta and right atrium with left-right shunt. A transesophageal echocardiogram (TEE) was performed to confirm the diagnosis of IE. Three sets of blood cultures were performed, with negative results, empirical therapy was managed and a decision for TEE-guided cardiac surgery was made. Discussion Fistula is a rare complication of IE representing the most insidious consequence of uncontrolled infection like BCNIE, a condition that has restricted the therapeutic possibilities to empirical therapy only and to early surgery. The TEE was instrumental in diagnosing right-sided infective endocarditis and allowing us to focus on the perivalvular spread of the infection in our case.

Blood Culture Negative Infective Endocarditis and Surgery: An Updated Review of the Literature

Blood Culture Negative Infective Endocarditis and Surgery: An Updated Review of the Literature

Expect the unexpected: endocarditis caused by Legionella feeleii.

We report a fatal case of Legionella feeleii endocarditis in a post-lung transplant patient. The diagnosis was delayed, as routine microbiological testing of nonrespiratory specimens does not account for extrapulmonary Legionella, and urine antigen testing only reliably detects Legionella pneumophila serogroup 1. This case also illustrates the utility of molecular sequencing for blood culture-negative endocarditis.

Culture-negative endocarditis with multifocal spread and flail mitral valve leaflet: a case report

Introduction: Blood culture-negative infective endocarditis is the condition in which a causative organism cannot be identified after inoculation of at least three samples using standard blood-culture systems for 7 days. It has a low reported incidence of about 2.5–31%. Causes may be infectious or non-infectious; use of prior antibiotic therapy is usually the leading factor. Case presentation: The authors present a case of true culture-negative endocarditis involving the mitral valve, with multiple foci of spread including brain, spleen, liver, and Intervertebral disc, which remained persistent despite treatment with intravenous broad-spectrum antibiotics on an inpatient and outpatient basis but eventually improved after upgrading alternative broad-spectrum antibiotic for an extended duration. The patient had complications in the form of a flail mitral valve with persistent mitral regurgitation, requiring mitra-clip placement. Discussion: Positive blood culture is one of the major diagnostic criteria to establish infective endocarditis. Patients may have persistent negative cultures due to previous antibiotic use, the presence of fastidious organisms, or the use of inappropriate techniques or media. Involvement of a multidisciplinary team, use of multimodal investigations, and appropriate antibiotic stewardship are crucial. Extended duration of treatment and upgrading antibiotics can be helpful next steps in highly suspicious cases. With multifocal spread as in our case, it further becomes challenging to control and treat the infection as it is frequently connected with higher morbidity and mortality. Conclusion: Blood culture-negative endocarditis is an entity that can present with early complications. It is diagnostically and therapeutically challenging to treat such patients. Multimodal approaches for early diagnosis and appropriate treatment are crucial owing to its high morbidity and mortality.

Blood culture-negative infective endocarditis caused by <i>Bartonella henselae</i> diagnosed through repeated echocardiography: A case report

Blood culture-negative infective endocarditis caused by <i>Bartonella henselae</i> diagnosed through repeated echocardiography: A case report

Fastidious Bacterial Pathogens in Replaced Heart Valves: The First Report of Bartonella quintana and Legionella steeli in Blood Culture-Negative Endocarditis from Iran

Background: Infectious endocarditis is a rare infectious disease of the cardiac endothelium, but blood culture-negative endocarditis (BCNE) should be considered. Objectives: This study aims to determine the prevalence of possible infectious agents of BCNE. Methods: Real-time PCR and PCR sequencing were used to identify Coxiella burnetii, Tropheryma whipplei, Brucella spp., Legionella spp., and Bartonella spp. 16srRNA sequencing was used for the samples with negative results of PCR sequencing and real-time PCR. Results: Among the 59 positive results, the rates of Bartonella spp., Legionella spp., and Brucella spp. were 8.5%, 5.1%, and 3.4%, respectively. C. burnetii and T. whipplei were not detected. 16srRNA sequencing revealed 1 Stenotrophomonas maltophilia, 1 Aeribacillus spp. and 1 uncultured bacterium. Conclusions: The rate of some bacteria that are difficult to detect with routine laboratory tests was high in our study, and it seems that hospitals should use dedicated technology to detect BCNE pathogens.

Uncommon pathogens causing infective endocarditis.

Infective endocarditis is caused by a wide range of aetiological agents. The microbiology, epidemiology, and treatment of this disease have changed considerably in the last two decades. Staphylococci and streptococci are known to be the classical causative agents; however, blood culture-negative endocarditis caused by fastidious and slow-growing organisms is now common. The list of uncommon pathogens causing endocarditis has expanded in recent years. This is a narrative literature review of the aetiological agents of endocarditis that are rarely encountered in clinical practice, their epidemiology, the characteristics of these pathogens, the clinical presentations of the cases, and their management.

Comparison of Blood-Based Shotgun and Targeted Metagenomic Sequencing for Microbiological Diagnosis of Infective Endocarditis.

Shotgun and targeted metagenomic sequencing have been shown in separate studies to be potentially useful for culture-free pathogen identification in blood and/or plasma of patients with infective endocarditis (IE). However, the 2 approaches have not been directly compared. The aim of this study was to compare shotgun metagenomic sequencing with targeted metagenomic sequencing (tMGS) for organism identification in blood or plasma of patients with IE. Patients with possible or definite IE were prospectively enrolled from October 2020 to July 2021. Shotgun metagenomic sequencing was performed with the Karius test, which uses microbial cell-free DNA (mcfDNA) sequencing to detect, identify, and quantitate DNA-based pathogens in plasma. tMGS was performed using a 16S ribosomal RNA (rRNA) polymerase chain reaction assay targeting the V1 to V3 regions of the 16S rRNA gene. Results were compared using the McNemar test of paired proportions. Samples from 34 patients were investigated. The Karius test was positive in 24/34 (71%), including 3/6 (50%) with blood culture-negative endocarditis (BCNE), which was not significantly different from the positivity rate of tMGS (P = .41). Results of the Karius test were concordant with tMGS in 75% of cases. The Karius test detected 2 cases of methicillin-resistant Staphylococcus aureus among the 7 S. aureus detections, in accordance with results of phenotypic susceptibility testing. The combination of blood cultures, the Karius test, and tMGS found a potential causative pathogen in 33/34 (97%), including 5/6 with BCNE. The Karius test and tMGS yielded comparable detection rates; however, beyond organism identification, the Karius test generated potentially useful antibiotic resistance data.

A Rare Case of HACEK Endocarditis in the Context of a Permanent Pacemaker

Introduction: Infective endocarditis (IE) is a serious medical condition that can lead to high morbidity and mortality rates. The prevalence of healthcare-associated IE is increasing due to the use of therapeutic devices, such as intravascular catheters and cardiac devices. The HACEK group of bacteria, are commonly found in human respiratory and genitourinary tracts, are low virulence and fastidious organisms that are associated with blood culture-negative endocarditis. Proper diagnosis requires a combination of clinical, microbiological, and imaging results. The following study presents a case of atypical device-associated IE caused by Haemophilus influenzae in a 56-year-old man with a permanent pacemaker. Methodology: description of a clinical problem, its diagnosis, management, and outcome, accompanied with a literature review. Conclusion: This study highlights the importance of considering the HACEK group of bacteria in culture-negative IE cases and the use of advanced imaging techniques in diagnosis to prevent further complications and improve patient outcomes.

Microbiological Etiology in Patients with IE Undergoing Surgery and for Patients with Medical Treatment Only: A Nationwide Study from 2010 to 2020.

Microbiological etiology has been associated with surgery for infective endocarditis (IE) during admission, especially Staphylococcus aureus. We aimed to compare patient characteristics, microbiological characteristics, and outcomes by treatment choice (surgery or not). We identified patients with first-time IE between 2010 and 2020 and examined the microbiological etiology of IE according to treatment choice. To identify factors associated with surgery during initial admission, we used the Aalen-Johansen estimator and an adjusted cause-specific Cox model. One-year mortality stratified by microbiological etiology and treatment choice was assessed using unadjusted Kaplan-Meier estimates and an adjusted Cox proportional hazard model. A total of 6255 patients were included, of which 1276 (20.4%) underwent surgery during admission. Patients who underwent surgery were younger (65 vs. 74 years) and less frequently had cerebrovascular disease, cardiovascular disease, diabetes, and chronic kidney disease. Patients with Staphylococcus aureus IE were less likely to undergo surgery during admission (13.6%) compared to all other microbiological etiologies. One-year mortality according to microbiological etiology in patients who underwent surgery was 7.0%, 5.3%, 5.5%, 9.6%, 13.2, and 11.2% compared with 24.2%, 19.1%, 27,6%, 25.2%, 21%, and 16.9% in patients who received medical therapy for Staphylococcus aureus, Streptococcus spp., Enterococcus spp., coagulase-negative Staphylococci, "other microbiological etiologies", and blood culture-negative infective endocarditis, respectively. Patients with IE who underwent surgery differed in terms of microbiology, more often having Streptococci than those who received medical therapy. Contrary to expectations, Staphylococcus aureus was more common among patients who received medical therapy only.

Case series of 12 Bartonella quintana endocarditis from the Southwest Indian Ocean.

Bartonella spp. are fastidious bacteria frequently identified as the cause of blood culture-negative (BCN) endocarditis. However, Bartonella infections are difficult to diagnose in routine laboratory testing and their incidence is probably underestimated. We investigated the epidemiological and clinical features of Bartonella endocarditis cases diagnosed between 2009 and 2021 on Reunion Island (Southwest Indian Ocean). We retrospectively included all patients diagnosed with Bartonella endocarditis at Reunion Island University Hospital during this period. Endocarditis was diagnosed on the basis of microbiological findings, including serological tests (IFA) and PCR on cardiac valves, and the modified Duke criteria. We used then the multispacer typing (MST) method to genotype the available Bartonella strains. We report 12 cases of B. quintana endocarditis on Reunion Island (83.3% in men, median patient age: 32 years). All the patients originated from the Comoros archipelago. The traditional risk factors for B. quintana infection (homelessness, alcoholism, exposure to body lice) were absent in all but two of the patients, who reported head louse infestations in childhood. Previous heart disease leading to valve dysfunction was recorded in 50% of patients. All patients underwent cardiac valve surgery and antimicrobial therapy with a regimen including doxycycline. All patients presented high C-reactive protein concentrations, anemia and negative blood cultures. The titer of IgG antibodies against Bartonella sp. exceeded 1:800 in 42% of patients. Specific PCR on cardiac valves confirmed the diagnosis of B. quintana endocarditis in all patients. Genotyping by the MST method was performed on four strains detected in preserved excised valves and was contributive for three, which displayed the MST6 genotype. Bartonella quintana is an important cause of infective endocarditis in the Comoros archipelago and should be suspected in patients with mitral valve dysfunction and BCN from this area.

Updates in Culture-Negative Endocarditis.

Blood culture-negative infective endocarditis (BCNE) is a challenging condition associated with significant morbidity and mortality. This review discusses the epidemiology, microbiology, diagnosis, and treatment of BCNE considering advancements in molecular diagnostics and increased access to cardiac surgery. BCNE can be categorized into bacterial endocarditis with sterilized blood cultures due to previous antibiotic treatment, endocarditis caused by fastidious microorganisms, and true BCNE caused by intracellular organisms that cannot be cultured using traditional techniques. Non-infectious causes such as nonbacterial thrombotic endocarditis should also be considered. Diagnostic approaches involve thorough patient history; blood and serum testing, including appropriate handling of blood cultures; serological testing; and molecular techniques such as targeted and shotgun metagenomic sequencing. Where available, evaluation of explanted cardiac tissue through histopathology and molecular techniques is crucial. The therapy for BCNE depends on the likely causative agent and the presence of prosthetic material, with surgical intervention often required.

"Let the Cat Out of the Heart": Clinical Characteristics of Patients Presenting With Blood Culture-Negative Endocarditis Due to Bartonella Species.

Patients with blood culture-negative endocarditis due to Bartonella infection frequently presented with fever, cytopenias, kidney failure, and positive PR3-ANCA. Bartonella IgG titers were variable. Patients commonly underwent surgery with overall low mortality.

Clinical Significance of a 16S-rDNA Analysis of Heart Valves in Patients with Infective Endocarditis: a Retrospective Study.

A substantial proportion of patients with infective endocarditis (IE) are subjected to heart valve surgery. Microbiological findings on valves are important both for diagnostics and for tailored antibiotic therapy, post-operatively. The aims of this study were to describe microbiological findings on surgically removed valves and to examine the diagnostic benefits of 16S-rDNA PCR and sequencing (16S-analysis). Adult patients who were subjected to heart valve surgery for IE between 2012 and 2021 at Skåne University Hospital, Lund, where a 16S-analysis had been performed on the valve, constituted the study population. Data were gathered from medical records, and the results from blood cultures, valve cultures, and 16S-analyses of valves were compared. A diagnostic benefit was defined as providing an agent in blood culture negative endocarditis, providing a new agent in episodes with positive blood cultures, or confirming one of the findings in episodes with a discrepancy between blood and valve cultures. 279 episodes in 272 patients were included in the final analysis. Blood cultures were positive in 259 episodes (94%), valve cultures in 60 episodes (22%), and 16S-analyses in 227 episodes (81%). Concordance between the blood cultures and the 16S-analysis was found in 214 episodes (77%). The 16S-analyses provided a diagnostic benefit in 25 (9.0%) of the episodes. In blood culture negative endocarditis, the 16S-analyses had a diagnostic benefit in 15 (75%) of the episodes. A 16S-analysis should be routinely performed on surgically removed valves in blood culture negative endocarditis. In patients with positive blood cultures, 16S-analysis may also be considered, as a diagnostic benefit was provided in some patients. IMPORTANCE This work demonstrates that it can be of importance to perform both cultures and analysis using 16S-rDNA PCR and sequencing of valves excised from patients undergoing surgery for infective endocarditis. 16S-analysis may help both to establish a microbiological etiology in cases of blood culture negative endocarditis and to provide help in situations where there are discrepancies between valve and blood cultures. In addition, our results show a high degree of concordance between blood cultures and 16S-analyses, indicating that the latter has a high sensitivity and specificity for the etiological diagnosis of endocarditis in patients who were subjected to heart valve surgery.

A Case of Blood Culture-Negative Infective Endocarditis Presenting as Recurrent Ischemic Stroke (P8-10.007)

<h3>Objective:</h3> We present a unique case of recurrent ischemic stroke in a patient with blood culture-negative bacterial endocarditis. <h3>Background:</h3> The incidence of infective endocarditis (IE) has steadily increased in the past decade. About 2–7% of IE cases have negative blood cultures, making it difficult to diagnose with worse resulting prognoses. The risk of neurological complications in culture-negative IE, such as stroke, are high and linked to poor clinical outcomes. However, there are limited data on the incidence of stroke as an isolated presenting symptom or on the rate of stroke recurrence in this population. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 57-year-old woman with a history of diabetes mellitus, hypertension, and coronary artery disease presented with recurrent multi-territorial ischemic strokes. Her initial work-up showed unclear etiology. A transesophageal echocardiogram was obtained and demonstrated a 0.5×1 cm mobile echodensity on the mitral valve, concerning for either thrombus or vegetation. Thrombophilic laboratory results displayed an indeterminate lupus anticoagulant cascade. As the patient lacked infectious symptoms with an extensive negative infectious workup, she was started on anticoagulation due to possible thrombotic source in the setting of thrombophilia. However, the patient suffered another ischemic stroke while fully anticoagulated. With this being her third stroke in a seven-month period, the patient underwent surgical resection of the lesion. At the time of surgery, the mass was noted to appear as an infectious vegetation, and she was treated with broad-spectrum antibiotics for presumed culture-negative endocarditis. The valve culture later grew <i>Staphylococcus epidermidis</i>. Daptomycin was continued and she has had no additional strokes to date. <h3>Conclusions:</h3> It is well-established that stroke is a common complication of IE. However, little has been documented about stroke as the presenting symptom in blood culture-negative IE. Therefore, it is important to maintain a high degree of suspicion for indolent infection to pursue additional work-up and prevent any delays in treatment. <b>Disclosure:</b> Ms. Chatfield has nothing to disclose. Ms. Braddick has nothing to disclose. Dr. Sobhani has nothing to disclose.

Infectious endocarditis caused by Bartonella henselae associated with infected pets: two case reports

BackgroundBlood culture-negative infective endocarditis is a potentially severe disease that can be associated with infectious agents such as Bartonella spp., Coxiella burnetti, Tropheryma whipplei, and some fungi.Case presentationReported here are two cases of blood culture-negative infective endocarditis in patients with severe aortic and mitral regurgitation in Brazil; the first case is a 47-year-old white man and the second is a 62-year-old white woman. Bartonella henselae deoxyribonucleic acid was detectable in the blood samples and cardiac valve with vegetation paraffin-fixed tissue samples. Additionally, an investigation was carried out on patients’ pets, within the context of One Health, and serum samples collected from cats and dogs were reactive by indirect immunofluorescence assay.ConclusionsEven though the frequency of bartonellosis in Brazil is unknown, physicians should be aware of the possibility of blood culture-negative infective endocarditis caused by Bartonella, particularly in patients with weight loss, kidney changes, and epidemiological history for domestic animals.

Prolonged Fever in a Child With Congenital Heart Disease and a Prosthetic Valve.

Prolonged Fever in a Child With Congenital Heart Disease and a Prosthetic Valve.

Blood Culture Negative Endocarditis: A Review of Laboratory Diagnostic Approaches

Infective endocarditis is a potentially fatal condition, and identifying the pathogen is crucial to optimizing antibiotic treatment. While a blood culture takes time and may yield negative results, it remains the gold standard for diagnosis, blood culture-negative endocarditis, which accounts for up to 20% of infective endocarditis cases, poses a clinical challenge with increasing mortality. To better understand the etiology of blood culture-negative infective endocarditis, we reviewed non-culture-based strategies and compared the results. Serology tests work best in limited pathogens, such as Coxiella burnetii and Bartonella infections. Most of the pathogens identified by broad-range PCR tests are Streptococcus spp, Staphylococcus spp and Propionibacterium spp. adding specific real-time PCR assays to the systematic PCR testing of patients with blood culture-negative endocarditis will increase the efficiency of diagnosis. Recently, metagenomic next-generation sequencing has also shown promising results.