Bartonella Species as a Cause of Culture-negative Endocarditis in South Africa 

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Methods : The Tygerberg Endocarditis cohort (TEC) study is a prospective cohort study of patients with confirmed or suspected IE presenting to Tygerberg Academic Hospital, Cape Town, South Africa. Results: To date, 44 patients have been included in this ongoing study. Fourteen of the 44 patients (31.8%) had BCNE. Further analysis of the patients with BCNE identified Bartonella species as the most common causative organism (n=6; 43%). Other causes included Mycoplasma species (n=2), C. burnetii (n=1), and non-bacterial thrombotic endocarditis due to anti-phospholipid syndrome (n=1). No cause could be identified in 4 of the 44 patients (9%). Bartonella quintana was identified with PCR of valvular tissue as the causative organism in 4 of the 5 patients that underwent urgent surgery. The patients with Bartonella IE (n=6) had an average age of 39 years with equal gender distribution The common clinical features were clubbing (n=5; 83%), anemia (n=4; 66.6%), haematuria (n=3; 50%), acute on chronic severe valvular lesion (n=3; 50%) and acute severe valvular lesion (n=2; 33.3%). The aortic valve was involved in 5 of 6 patients. During a mean follow-up period of 251 days after diagnosis, no major adverse events occurred. Conclusion: Bartonella IE is an important cause of BCNE in the Western Cape of South Africa. Imaging findings of significant valvular destruction with large vegetations on the aortic valve not affected by pre-existing congenital or rheumatic valve disease, should raise the suspicion of Bartonella IE. General Microbiology Infectious Diseases Infective endocarditis blood culture negative endocarditis Bartonella quintana Bartonella henselae Figures Figure 1 Figure 2 Summary Bartonella species is an important cause of blood culture negative endocarditis in the Western Cape of South Africa. Imaging findings of significant valvular destruction with large vegetations on the aortic valve should raise the suspicion of Bartonella associated infective endocarditis. Background Infective endocarditis (IE) is defined as an infection involving the endocardial surface of the heart. This can primarily affect native heart valves (native valve endocarditis or NVE), prosthetic heart valves (prosthetic valve endocarditis – PVE), non-valvular endocardial surfaces (such as IE affecting ventricular septal defects) or any cardiac prosthetic devices.(1,2) The characteristics of IE have evolved in developed nations with a doubling of patient age, an increase in the prevalence of patients with IE due to Staphylococcus aureus in the setting of normal or non-rheumatic valves and a decrease in the prevalence of blood culture negative endocarditis (BCNE).(2,3) Data regarding the causes and epidemiology of IE in the developing world and specifically South Africa are limited. Current reports from South Africa suggest IE is still a disease of young patients with underlying rheumatic heart disease, predominantly caused by the viridans group streptococci and with a high rate of BCNE.(1,4) The postulated reason for the high rate of BCNE in the published South African literature has been the high rate of antibiotic use prior to blood culture sampling.(4) Data from the developed world would suggest that organisms that are difficult to culture and/or identify with standard laboratory methods are the commonest cause of BCNE. These organisms vary according to region, with developed countries reporting mostly Coxiella burnetii as a causative organism in cases of IE previously considered as BCNE.(1) Limited data is available for South Africa, but reports from Algeria (a developing country) suggest Bartonella species is a more common cause of BCNE than C. burnetii .(7) BCNE is associated with a higher rate of in-hospital adverse events, although recent publications have suggested similar long-term outcomes when compared to blood culture positive patients. (8,9) Bartonella species are small Gram-negative bacilli that are generally transmitted by arthropod vectors. These fastidious intracellular bacteria cause various clinical syndromes and diagnosis is challenging due to difficulties isolating the organism using traditional culture methods.(10) Bartonella quintana is mostly associated with trench fever, IE and bacillary angiomatosis whereas Bartonella henselae is associated with cat scratch disease, bacillary angiomatosis and less commonly, with IE. B. quintana infection is often reported in homeless persons infested with body lice as compared to B. henselae infection which is usually associated with contact with cats. Single cases of other Bartonella species causing IE have been reported.(10,11) The Tygerberg Endocarditis Cohort (TEC) study is a prospective cohort study of patients with definite or suspected IE according to the European Society of Cardiology (ESC) criteria.(2) All patients included are managed by an Endocarditis Heart Team with a set protocol to detect the causative organism as per the current ESC guidelines.(2) Tygerberg Academic Hospital is a public sector tertiary referral centre for a network of 17 hospitals and serves a population of approximately 2.4 million people.(12) Methods All patients referred to the Division of Cardiology, Department of Medicine at Tygerberg Hospital in Cape Town, South Africa, with definite or suspected IE from November 2019 to August 2020 were included in this ongoing study. All patients underwent standard transthoracic echocardiography (TTE) with the majority also undergoing transoesophageal echocardiography (TEE) in the absence of identifiable contra-indications to TEE.(13,14) A stepwise protocol for organism detection was utilised to identify the common causative organisms of IE and to minimize the incidence of BCNE (Figure 1). Further management and analysis of the samples were done according to current published guidelines.(2) Patients without an identified organism using standard culture techniques after 5 days, were defined as having BCNE. All BCNE patients underwent further venous blood analysis for further testing, including: Serology for detection of IgM and IgG antibodies to Bartonella species , Brucella species , C. burnetii, Legionella pneumophila and Mycoplasma pneumoniae Antibody testing for antinuclear antibodies (ANF) and anti-cardiolipin antibodies (ACLA) Direct polymerase chain reaction (PCR) was performed on negative blood culture bottles for detection of the universal bacterial 16S rRNA and fungal 18S rRNA genes, followed by sequencing to identify the amplified DNA product. A sample of heart valve tissue was collected from all patients who required surgery and this was submitted for: All patients are treated by an Endocarditis team according to the current ESC guidelines.(2) Results To date, 44 patients have been included in this ongoing study. Fourteen of the 44 patients (31.8%) had BCNE. Further analysis of the patients with BCNE identified Bartonella species as the most common causative organism (n=6; 43%). Other causes included Mycoplasma species (n=2), C. burnetii (n=1), and non-bacterial thrombotic endocarditis due to anti-phospholipid syndrome (n=1). No cause could be identified in 4 of the 44 patients (9%). Two of the 4 patients had suspected Mycobacterium tuberculosis associated IE based on typical clinical and echocardiographic features, but without microbiological confirmation.(1) The patients with Bartonella IE (n=6) had an average age of 39 years with equal gender distribution (Table 1). The common clinical features were clubbing (n=5; 83%), anemia (n=4; 66.6%), haematuria (n=3; 50%), acute on chronic severe valvular lesion (n=3; 50%) and acute severe valvular lesion (n=2; 33.3%). Although echocardiography identified significant valvular destruction in all patients, no pre-existing underlying structural valve disease (rheumatic valve disease or congenital abnormalities) was identified. The aortic valve was involved in 5 of 6 patients. Acute severe aortic regurgitation was confirmed in 2 patients, acute on chronic severe aortic regurgitation in 2 patients, chronic severe aortic regurgitation in one patient and acute severe mitral regurgitation in one patient. Vegetation size ranged from 10-15mm on linear measurement with an average circumference of 28mm. Only one patient had a raised white cell count (WCC). C-reactive protein (CRP) levels were mildly raised with only one value above 50. Two of our 6 patients were HIV-positive; one was on antiretroviral treatment with undetectable viral load and one had a CD4 count of more than 1000 per microliter of blood. Four patients (66%) had low complement levels (Table 2). B. quintana and B. henselae IgG and IgM were detected by an immunofluorescence assay (IFA). IgG was positive in all patients with titres ranging from 1:256 to 1:512, while IgM was positive in 5 of the 6 patients. The 16S and 18S PCRs performed on blood cultures were negative in all patients. Both patients with acute severe aortic regurgitation underwent emergency valve replacement, 3 of the other 4 patients underwent urgent/inpatient valve replacement. Valve repair was not possible in one patient. Sequencing of the 16S PCR product from valve tissue identified B. quintana in 4 of the 5 patients who had surgery. The patients who underwent surgery survived their hospital stay and were discharged home on oral doxycycline. One patient declined surgery but successfully completed 3 months of oral doxycycline. During a mean follow-up period of 251 days after diagnosis, no major adverse events (death, embolic events, renal failure requiring dialysis, or rehospitalization) occurred. Discussion This is the first study that identifies Bartonella species as an important cause of BCNE in the Western Cape province of South Africa. Previous cohort studies of patients with IE in the Western Cape and South Africa overall have not reported Bartonella species as a cause of IE.(4–6,15) The first case was described in 1993 and another case was reported recently.(16,17) Our findings are in keeping with data from other developing countries where Bartonella species are the most common cause of BCNE contrasting with developed countries that report C. burnetii as the commonest cause of BCNE.(7,11,18) The reasons for the lack of reporting of Bartonella species as a cause of BCNE in South Africa are probably multifactorial. We postulate that our systematic approach to organism detection, including serology and newer diagnostic modalities such as PCR performed on valves, explains this new finding, rather than the emergence of Bartonella species as a new cause of BCNE in South Africa. Should this be the case, it follows that a large group of patients previously labelled as BCNE were not adequately treated for Bartonella IE and this may have contributed to the adverse outcome of these patients.(8,9) Our data would suggest that Bartonella IE, if adequately treated, has a favourable in-hospital and short term outcome in keeping with other case series.(18,19) PCR performed on blood and/or heart valves remains the gold standard for detection and identification of Bartonella to species level in patients with BCNE. Different techniques are available for analysis of heart valves; in this study, 16S PCR and sequencing of amplified bacterial DNA were used, although some reports suggest that real time PCR (RT-PCR) is more sensitive.(11) In our series, we identified B. quintana as the causative species in 4 of the 5 patients who underwent surgery. Of the 30 patients with culture positive endocarditis, 18 underwent valve surgery. None of these cases were PCR positive for Bartonella species on their valve tissue. Two patients were diagnosed with Bartonella-associated IE without PCR confirmation on blood or heart valve. The decision was made by the Endocarditis team on the basis of the typical clinical features, elevated serology titres and the absence of another causes in spite of a set protocol for organism detection. Currently criteria is lacking for the diagnosis of Bartonella IE if PCR on both the blood and heart valves is negative or unavailable in the setting of typical clinical and imaging findings and suggestive serology. Different serological cut-offs for the diagnosis of Bartonella IE has been suggested(11), with higher titers of IgG increasing the positive predictive value of serology assays. Serum samples of healthy volunteers typically have IgG titres by IFA of less than 1:128 and IgM titres less than 1:20, with no IgG titres above 1:256.(20) An IgM titre of more than 1:20 with an IgG titre of more than 1:128 suggest active Bartonella infection. We suggest that elevated Bartonella antibody titres in the setting of a typical clinical and imaging profile in the absence of another cause (after a set protocol for organism detection was followed), be utilised for the diagnosis (and thus initiation of therapy) of Bartonella IE. Serology for B. henselae and B. quintana is not very useful in distinguishing between species due to the high rate of cross-reactivity between the assays.(11) Although it is reported that the likely causative organism will have higher titers by serology(20), in our series of 4 patients with PCR-confirmed B. quintana IE, the IgG titres for B. quintana was either equal or lower than the IgG titres for B. henselae , while the B. quintana IgM titres were either similar, higher or lower than B. henselae IgM titres, suggesting that it is less helpful in distinguishing between Bartonella species. Previous case reports from South Africa and a case series from the United States also identified B. quintana as the causative species in BCNE.(16,17,21) A case series from Japan identified B. henselae as the causative species in five cases of BCNE.(19) B. henselae has been detected on blood PCR in up to 10% of HIV-positive patients in South Africa whereas no cases were detected in the non-HIV infected control cohort. No cases of IE due to B. henselae from South Africa has been published. The treatment for the different species of Bartonella is similar and currently no evidence is available to suggest the outcome of Bartonella IE is influenced by the specific causative species. The cross-reactivity of the serological tests for the different Bartonella species extend to patients with other causes of BCNE, including C. burnetii, Brucella and Mycoplasma species.(22) One of our patients with confirmed Mycoplasma hominis IE also had positive serology for B. henselae , although the IgG titre was less than 1:256. This finding puts into perspective the importance of performing PCR on both blood and valve tissue to confirm the causative organism in patients with BCNE, even if serology is positive for Bartonella, Brucella, Coxiella or Mycoplasma. Although the 16S PCR on blood was negative in all our patients, it remains important to detect organisms associated with BCNE (e.g. Mycoplasma) that might cause false-positive serology. The clinical features of the patients with Bartonella IE had significant overlap with the known features of IE caused by the usual organisms, with clubbing, anaemia and haematuria being the most common.(4) In all but one of the patients, the aortic valve was involved, which is in keeping with previous reports.(16,21) All patients had hemodynamically severe incompetence of either the aortic (n=5) or mitral (n=1) valve with clinical features of acute (n=2), acute on chronic (n=3) or chronic (n=1) incompetence. Historically, acute IE and acute valvular incompetence is associated with S. aureus IE and these patients often do not demonstrate the classical findings of clubbing and anemia as these features take time to develop.(23) In our series, patients with acute valve lesions had both clubbing and anemia; clubbing was also present in all of the patients with acute on chronic valve lesions. This would suggest a significant time from infection/bacteraemia to presentation, even though patients present with acute or acute on chronic valve incompetence. We postulate that patients with Bartonella IE has an early phase with minimal symptoms and low-grade underlying bacteraemia during which time the patient develops clubbing and anaemia of chronic disease. Patients only seek medical attention at the time of significant valvular destruction with the associated sequalae of dyspnea and hemodynamic compromise. The majority of patients had severe destruction of the aortic valve with no evidence of underlying congenital heart/valve disease (e.g. bicuspid aortic valve, ventricular septal defect) or rheumatic valve disease (Figure 2). The propensity of Bartonella species to involve the aortic valve is well documented, although no clear explanation exists for this finding.(18) Maximum vegetation length by two dimensional echocardiography of 10mm or more in patients with left-sided IE is associated with an increased risk of embolic events. Although large vegetations were observed in all our patients, no embolic events occurred.(24) In contrast to other causes of IE of the aortic valve, no peri-annular extension, e.g. peri-aortic abscess formation was noted. The fact that most patients underwent surgery early and were on appropriate antimicrobial therapy may have contributed to this finding. Due to the severe destruction of the aortic valve, 4 of 5 patients underwent aortic valve replacement with a mechanical valve. Mitral valve repair was attempted in the single patient with severe mitral regurgitation, but was converted intra-operatively to mitral valve replacement due to extensive tissue destruction. It would be difficult to draw meaningful conclusions from this small number of patients, but it seems that patients with Bartonella IE have a reasonably good short term outcome in spite of the significant valvular destruction and large vegetations observed with echocardiography. Conclusion Bartonella IE is an important cause of BCNE in the Western Cape of South Africa. A systematic approach to organism detection in patients with suspected or confirmed IE is essential for the diagnosis of the causative organism in patients with BCNE. Imaging findings of significant valvular destruction with large vegetations on the aortic valve not affected by pre-existing congenital or rheumatic valve disease, should raise the suspicion of Bartonella IE. Early initiation of appropriate antimicrobial therapy combined with early surgery seems to provide a good in-hospital and short term outcome. Declarations Funding : no funding to declare Conflicts of interest/Competing interests : None Ethics approval : Ethics approval was obtained from the committee for Human Research of the Faculty of Medicine, Stellenbosch University, Cape Town (ID 10660) Consent to participate : All patients provided written, informed consent. Consent for publication : The authors consent to publication of the data if accepted. Patients consented to the publication of the data and images. Availability of data and material : All data is securely stored on a digital database that is password protected. Data is available for review. References Pecoraro AJ, Doubell AF. Infective endocarditis in South Africa. Cardiovasc Diagn Ther [Internet]. 2020 Apr [cited 2020 Jun 2];10(2):252–61. Available from: http://cdt.amegroups.com/article/view/26995/30160 Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta J-P, Del Zotti F, et al. 2015 ESC Guidelines for the management of infective endocarditis. 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Demographic information, clinical and imaging findings Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Demographic information Age (years) 39 26 36 41 57 37 Sex Male Female Female Male Male Female Rural/Urban Rural Urban Urban Rural Urban Rural Housing Informal Formal Homeless Formal Formal Informal Clinical and imaging features Clubbing Yes Yes Yes No Yes Yes Anemia Yes No Yes Yes Yes No Hematuria No No No Yes Yes Yes Valve involvement Aortic Aortic Mitral Aortic Aortic Aortic Hemodynamic lesion Acute Acute on chronic Acute on chronic Chronic Acute Acute on chronic Vegetation length (mm) 15 12 10 11 10 10 Vegetation circumference (mm) 47 29 22 25 25 22 Vegetation number Multiple Multiple Single Multiple Multiple Multiple Pre-existing valvular structure Normal Normal Normal Normal Normal Normal Table 2. Special investigations and surgical outcome Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Special investigations B. quintana IgG Titre Positive 1:256 Positive 1:256 Positive 1:512 Positive 1:256 Positive 1:512 Positive 1:256 B. quintana IgM Titre Negative Positive 1:256 Positive 1:64 Positive 1:128 Positive 1:512 Positive 1:64 B. henselae IgG Titre Positive 1:256 Positive 1:256 Positive 1:512 Positive 1:512 Positive 1:512 Positive 1:256 B. henselae IgM Titre Negative Positive 1:64 Positive 1:64 Positive 1:64 Positive 1:512 Positive 1:128 16S PCR on valve tissue B. quintana Not done Negative B. quintana B. quintana B. quintana 16S PCR on blood cultures Negative Negative Negative Negative Negative Negative HIV status Positive Positive Negative Negative Negative Negative CRP 50 37 209 22 33 12 WCC (per microliter) 7700 10000 27600 7300 3150 8800 Complement level Normal Low Normal Low Low low Valve replaced Aortic Refused Mitral Aortic Aortic Aortic In-hospital mortality No No No No No No Current follow-up period (days) 369 128 352 306 226 130 Cite Share Download PDF Status: Published Journal Publication published 07 Apr, 2021 Read the published version in European Journal of Clinical Microbiology & Infectious Diseases → Version 1 posted Reviews received at journal 14 Feb, 2021 Reviewers invited by journal 09 Feb, 2021 First submitted to journal 13 Jan, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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01:39:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-230749/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-230749/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10096-021-04239-w","type":"published","date":"2021-04-07T19:07:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":5974740,"identity":"0c5f2a20-b99b-4dc3-ab73-63df831b897c","added_by":"auto","created_at":"2021-02-15 16:34:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58127,"visible":true,"origin":"","legend":"Protocol for organism detection","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-230749/v1/c399e39e53ff5c4a99c59f59.jpg"},{"id":5974961,"identity":"43c1dd9f-8a80-42ed-be67-82f23178ed00","added_by":"auto","created_at":"2021-02-15 16:37:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":62767,"visible":true,"origin":"","legend":"Parasternal long axis view of the aortic valve of patient 1, 2, 4-6 demonstrating severe valve destruction with large vegetations","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-230749/v1/c036303baef4bf405ac351db.jpg"},{"id":13661337,"identity":"b7832de3-a4fc-461f-8afb-5a87febe6872","added_by":"auto","created_at":"2021-09-17 10:28:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":403565,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-230749/v1/b3b1f12b-23e2-49e0-b97e-8a150dc8941f.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eBartonella Species as a Cause of Culture-negative Endocarditis in South Africa\u0026nbsp;\u003c/p\u003e","fulltext":[{"header":"Summary","content":"\u003cp\u003e\u003cem\u003eBartonella species\u003c/em\u003e is an important cause of blood culture negative endocarditis in the Western Cape of South Africa. Imaging findings of significant valvular destruction with large vegetations on the aortic valve should raise the suspicion of \u003cem\u003eBartonella \u003c/em\u003eassociated infective endocarditis.\u0026nbsp;\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eInfective endocarditis (IE) is defined as an infection involving the endocardial surface of the heart. This can primarily affect native heart valves (native valve endocarditis or NVE), prosthetic heart valves (prosthetic valve endocarditis \u0026ndash; PVE), non-valvular endocardial surfaces (such as IE affecting ventricular septal defects) or any cardiac prosthetic devices.(1,2) The characteristics of IE have evolved in developed nations with a doubling of patient age, an increase in the prevalence of patients with IE due to \u003cem\u003eStaphylococcus\u003c/em\u003e\u003cem\u003e aureus\u003c/em\u003e in the setting of normal or non-rheumatic valves and a decrease in the prevalence of blood culture negative endocarditis (BCNE).(2,3) Data regarding the causes and epidemiology of IE in the developing world and specifically South Africa are limited. Current reports from South Africa suggest IE is still a disease of young patients with underlying rheumatic heart disease, predominantly caused by the viridans group streptococci and with a high rate of BCNE.(1,4) The postulated reason for the high rate of BCNE in the published South African literature has been the high rate of antibiotic use prior to blood culture sampling.(4) Data from the developed world would suggest that organisms that are difficult to culture and/or identify with standard laboratory methods are the commonest cause of BCNE. These organisms vary according to region, with developed countries reporting mostly \u003cem\u003eCoxiella burnetii\u003c/em\u003e as a causative organism in cases of IE previously considered as BCNE.(1) Limited data is available for South Africa, but reports from Algeria (a developing country) suggest \u003cem\u003eBartonella \u003c/em\u003especies is a more common cause of BCNE than \u003cem\u003eC. burnetii\u003c/em\u003e.(7) BCNE is associated with a higher rate of in-hospital adverse events, although recent publications have suggested similar long-term outcomes when compared to blood culture positive patients. (8,9)\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBartonella\u003c/em\u003e species are small Gram-negative bacilli that are generally transmitted by arthropod vectors. These fastidious intracellular bacteria cause various clinical syndromes and diagnosis is challenging due to difficulties isolating the organism using traditional culture methods.(10) \u003cem\u003eBartonella quintana\u003c/em\u003e is mostly associated with trench fever, IE and bacillary angiomatosis\u003cem\u003e whereas Bartonella henselae\u003c/em\u003e is associated with cat scratch disease, bacillary angiomatosis and less commonly, with IE. \u003cem\u003eB. quintana\u003c/em\u003e infection is often reported in homeless persons infested with body lice as compared to \u003cem\u003eB. henselae\u003c/em\u003e infection which is usually associated with contact with cats. Single cases of other \u003cem\u003eBartonella\u003c/em\u003e species causing IE have been reported.(10,11)\u003c/p\u003e\n\u003cp\u003eThe Tygerberg Endocarditis Cohort (TEC) study is a prospective cohort study of patients with definite or suspected IE according to the European Society of Cardiology (ESC) criteria.(2) All patients included are managed by an Endocarditis Heart Team with a set protocol to detect the causative organism as per the current ESC guidelines.(2) Tygerberg Academic Hospital is a public sector tertiary referral centre for a network of 17 hospitals and serves a population of approximately 2.4 million people.(12)\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003eAll patients referred to the Division of Cardiology, Department of Medicine at Tygerberg Hospital in Cape Town, South Africa, with definite or suspected IE from November 2019 to August 2020 were included in this ongoing study. All patients underwent standard transthoracic echocardiography (TTE) with the majority also undergoing transoesophageal echocardiography (TEE) in the absence of identifiable contra-indications to TEE.(13,14) A stepwise protocol for organism detection was utilised to identify the common causative organisms of IE and to minimize the incidence of BCNE (Figure 1). Further management and analysis of the samples were done according to current published guidelines.(2) Patients without an identified organism\u0026nbsp;using standard culture techniques after 5 days, were defined as having BCNE.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll BCNE patients underwent further venous blood analysis for further testing, including:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eSerology for detection of IgM and IgG antibodies to \u003cem\u003eBartonella \u003c/em\u003especies\u003cem\u003e, Brucella \u003c/em\u003especies\u003cem\u003e, C. burnetii, Legionella pneumophila\u003c/em\u003e and \u003cem\u003eMycoplasma pneumoniae\u003c/em\u003e\u003c/li\u003e\n\u003cli\u003eAntibody testing for antinuclear antibodies (ANF) and anti-cardiolipin antibodies (ACLA)\u003c/li\u003e\n\u003cli\u003eDirect polymerase chain reaction (PCR) was performed on negative blood culture bottles for detection of the universal bacterial 16S rRNA and fungal 18S rRNA genes, followed by sequencing to identify the amplified DNA product.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eA sample of heart valve tissue was collected from all patients who required surgery and this was submitted for:\u003c/p\u003e\n\u003cp\u003eAll patients are treated by an Endocarditis team according to the current ESC guidelines.(2)\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTo date, 44 patients have been included in this ongoing study. Fourteen of the 44 patients (31.8%) had BCNE. Further analysis of the patients with BCNE identified \u003cem\u003eBartonella \u003c/em\u003especies as the most common causative organism (n=6; 43%). Other causes included \u003cem\u003eMycoplasma \u003c/em\u003especies (n=2), \u003cem\u003eC. burnetii\u003c/em\u003e (n=1), and non-bacterial thrombotic endocarditis due to anti-phospholipid syndrome (n=1). No cause could be identified in 4 of the 44 patients (9%). Two of the 4 patients had suspected \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e associated IE based on typical clinical and echocardiographic features, but without microbiological confirmation.(1)\u003c/p\u003e\n\u003cp\u003eThe patients with Bartonella IE (n=6) had an average age of 39 years with equal gender distribution (Table 1). The common clinical features were clubbing (n=5; 83%), anemia (n=4; 66.6%), haematuria (n=3; 50%), acute on chronic severe valvular lesion (n=3; 50%) and acute severe valvular lesion (n=2; 33.3%).\u003c/p\u003e\n\u003cp\u003eAlthough echocardiography identified significant valvular destruction in all patients, no pre-existing underlying structural valve disease (rheumatic valve disease or congenital abnormalities) was identified. The aortic valve was involved in 5 of 6 patients. Acute severe aortic regurgitation was confirmed in 2 patients, acute on chronic severe aortic regurgitation in 2 patients, chronic severe aortic regurgitation in one patient and acute severe mitral regurgitation in one patient.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVegetation size ranged from 10-15mm on linear measurement with an average circumference of 28mm. Only one patient had a raised white cell count (WCC). C-reactive protein (CRP) levels were mildly raised with only one value above 50. Two of our 6 patients were HIV-positive; one was on antiretroviral treatment with undetectable viral load and one had a CD4 count of more than 1000 per microliter of blood. Four patients (66%) had low complement levels (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eB. quintana \u003c/em\u003eand\u003cem\u003e B. henselae\u003c/em\u003e IgG and IgM were detected by an immunofluorescence assay (IFA). IgG was positive in all patients with titres ranging from 1:256 to 1:512, while IgM was positive in 5 of the 6 patients. The 16S and 18S PCRs performed on blood cultures were negative in all patients. Both patients with acute severe aortic regurgitation underwent emergency valve replacement, 3 of the other 4 patients underwent urgent/inpatient valve replacement. Valve repair was not possible in one patient. Sequencing of the 16S PCR product from valve tissue identified \u003cem\u003eB. quintana\u003c/em\u003e in 4 of the 5 patients who had surgery. The patients who underwent surgery survived their hospital stay and were discharged home on oral doxycycline. One patient declined surgery but successfully completed 3 months of oral doxycycline. During a mean follow-up period of 251 days after diagnosis, no major adverse events (death, embolic events, renal failure requiring dialysis, or rehospitalization) occurred.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first study that identifies \u003cem\u003eBartonella\u003c/em\u003e species as an important cause of BCNE in the Western Cape province of South Africa. Previous cohort studies of patients with IE in the Western Cape and South Africa overall have not reported \u003cem\u003eBartonella\u003c/em\u003e species as a cause of IE.(4\u0026ndash;6,15) The first case was described in 1993 and another case was reported recently.(16,17) Our findings are in keeping with data from other developing countries where \u003cem\u003eBartonella\u003c/em\u003e species are the most common cause of BCNE contrasting with developed countries that report \u003cem\u003eC. burnetii\u003c/em\u003e as the commonest cause of BCNE.(7,11,18) The reasons for the lack of reporting of \u003cem\u003eBartonella\u003c/em\u003e species as a cause of BCNE in South Africa are probably multifactorial. We postulate that our systematic approach to organism detection, including serology and newer diagnostic modalities such as PCR performed on valves, explains this new finding, rather than the emergence of \u003cem\u003eBartonella\u003c/em\u003e species as a new cause of BCNE in South Africa. Should this be the case, it follows that a large group of patients previously labelled as BCNE were not adequately treated for Bartonella IE and this may have contributed to the adverse outcome of these patients.(8,9) Our data would suggest that Bartonella IE, if adequately treated, has a favourable in-hospital and short term outcome in keeping with other case series.(18,19)\u003c/p\u003e\n\u003cp\u003ePCR performed on blood and/or heart valves remains the gold standard for detection and identification of Bartonella to species level in patients with BCNE. Different techniques are available for analysis of heart valves; in this study, 16S PCR and sequencing of amplified bacterial DNA were used, although some reports suggest that real time PCR (RT-PCR) is more sensitive.(11) In our series, we identified \u003cem\u003eB. quintana\u003c/em\u003e as the causative species in 4 of the 5 patients who underwent surgery. Of the 30 patients with culture positive endocarditis, 18 underwent valve surgery. None of these cases were PCR positive for Bartonella species on their valve tissue.\u003c/p\u003e\n\u003cp\u003eTwo patients were diagnosed with Bartonella-associated IE without PCR confirmation on blood or heart valve. The decision was made by the Endocarditis team on the basis of the typical clinical features, elevated serology titres and the absence of another causes in spite of a set protocol for organism detection. Currently criteria is lacking for the diagnosis of Bartonella IE if PCR on both the blood and heart valves is negative or unavailable in the setting of typical clinical and imaging findings and suggestive serology. Different serological cut-offs for the diagnosis of Bartonella IE has been suggested(11), with higher titers of IgG increasing the positive predictive value of serology assays. Serum samples of healthy volunteers typically have IgG titres by IFA of less than 1:128 and IgM titres less than 1:20, with no IgG titres above 1:256.(20) An IgM titre of more than 1:20 with an IgG titre of more than 1:128 suggest active Bartonella infection. We suggest that elevated Bartonella antibody titres in the setting of a typical clinical and imaging profile in the absence of another cause (after a set protocol for organism detection was followed), be utilised for the diagnosis (and thus initiation of therapy) of Bartonella IE.\u003c/p\u003e\n\u003cp\u003eSerology for \u003cem\u003eB. henselae\u003c/em\u003e and \u003cem\u003eB. quintana\u003c/em\u003e is not very useful in distinguishing between species due to the high rate of cross-reactivity between the assays.(11) Although it is reported that the likely causative organism will have higher titers by serology(20), in our series of 4 patients with PCR-confirmed \u003cem\u003eB. quintana\u003c/em\u003e IE, the IgG titres for \u003cem\u003eB. quintana\u003c/em\u003e was either equal or lower than the IgG titres for \u003cem\u003eB. henselae\u003c/em\u003e, while the \u003cem\u003eB. quintana\u003c/em\u003e IgM titres were either similar, higher or lower than \u003cem\u003eB. henselae\u003c/em\u003e IgM titres, suggesting that it is less helpful in distinguishing between \u003cem\u003eBartonella\u003c/em\u003e species.\u003c/p\u003e\n\u003cp\u003ePrevious case reports from South Africa and a case series from the United States also identified \u003cem\u003eB. quintana\u003c/em\u003e as the causative species in BCNE.(16,17,21) A case series from Japan identified \u003cem\u003eB. henselae\u003c/em\u003e as the causative species in five cases of BCNE.(19) \u003cem\u003eB. henselae\u003c/em\u003e has been detected on blood PCR in up to 10% of HIV-positive patients in South Africa whereas no cases were detected in the non-HIV infected control cohort. No cases of IE due to \u003cem\u003eB. henselae\u003c/em\u003e from South Africa has been published. The treatment for the different species of Bartonella is similar and currently no evidence is available to suggest the outcome of Bartonella IE is influenced by the specific causative species.\u003c/p\u003e\n\u003cp\u003eThe cross-reactivity of the serological tests for the different \u003cem\u003eBartonella\u003c/em\u003e species extend to patients with other causes of BCNE, including \u003cem\u003eC. burnetii, Brucella \u003c/em\u003eand\u003cem\u003e Mycoplasma \u003c/em\u003especies.(22) One of our patients with confirmed \u003cem\u003eMycoplasma hominis\u003c/em\u003e IE also had positive serology for \u003cem\u003eB. henselae\u003c/em\u003e, although the IgG titre was less than 1:256. This finding puts into perspective the importance of performing PCR on both blood and valve tissue to confirm the causative organism in patients with BCNE, even if serology is positive for Bartonella, Brucella, Coxiella or Mycoplasma. Although the 16S PCR on blood was negative in all our patients, it remains important to detect organisms associated with BCNE (e.g. Mycoplasma) that might cause false-positive serology.\u003c/p\u003e\n\u003cp\u003eThe clinical features of the patients with Bartonella IE had significant overlap with the known features of IE caused by the usual organisms, with clubbing, anaemia and haematuria being the most common.(4) In all but one of the patients, the aortic valve was involved, which is in keeping with previous reports.(16,21) All patients had hemodynamically severe incompetence of either the aortic (n=5) or mitral (n=1) valve with clinical features of acute (n=2), acute on chronic (n=3) or chronic (n=1) incompetence. Historically, acute IE and acute valvular incompetence is associated with \u003cem\u003eS. aureus \u003c/em\u003eIE and these patients often do not demonstrate the classical findings of clubbing and anemia as these features take time to develop.(23) In our series, patients with acute valve lesions had both clubbing and anemia; clubbing was also present in all of the patients with acute on chronic valve lesions. This would suggest a significant time from infection/bacteraemia to presentation, even though patients present with acute or acute on chronic valve incompetence. We postulate that patients with Bartonella IE has an early phase with minimal symptoms and low-grade underlying bacteraemia during which time the patient develops clubbing and anaemia of chronic disease. Patients only seek medical attention at the time of significant valvular destruction with the associated sequalae of dyspnea and hemodynamic compromise.\u003c/p\u003e\n\u003cp\u003eThe majority of patients had severe destruction of the aortic valve with no evidence of underlying congenital heart/valve disease (e.g. bicuspid aortic valve, ventricular septal defect) or rheumatic valve disease (Figure 2). The propensity of \u003cem\u003eBartonella\u003c/em\u003e species to involve the aortic valve is well documented, although no clear explanation exists for this finding.(18)\u003c/p\u003e\n\u003cp\u003eMaximum vegetation length by two dimensional echocardiography of 10mm or more in patients with left-sided IE is associated with an increased risk of embolic events. Although large vegetations were observed in all our patients, no embolic events occurred.(24) In contrast to other causes of IE of the aortic valve, no peri-annular extension, e.g. peri-aortic abscess formation was noted. The fact that most patients underwent surgery early and were on appropriate antimicrobial therapy may have contributed to this finding. Due to the severe destruction of the aortic valve, 4 of 5 patients underwent aortic valve replacement with a mechanical valve. Mitral valve repair was attempted in the single patient with severe mitral regurgitation, but was converted intra-operatively to mitral valve replacement due to extensive tissue destruction. It would be difficult to draw meaningful conclusions from this small number of patients, but it seems that patients with Bartonella IE have a reasonably good short term outcome in spite of the significant valvular destruction and large vegetations observed with echocardiography.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e\u003cem\u003eBartonella IE\u003c/em\u003e is an important cause of BCNE in the Western Cape of South Africa. A systematic approach to organism detection in patients with suspected or confirmed IE is essential for the diagnosis of the causative organism in patients with BCNE. Imaging findings of significant valvular destruction with large vegetations on the aortic valve not affected by pre-existing congenital or rheumatic valve disease, should raise the suspicion of Bartonella IE. Early initiation of appropriate antimicrobial therapy combined with early surgery seems to provide a good in-hospital and short term outcome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: no funding to declare\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u003c/strong\u003e: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e: Ethics approval was obtained from the committee for Human Research of the Faculty of Medicine, Stellenbosch University, Cape Town (ID 10660)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e: All patients provided written, informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: The authors consent to publication of the data if accepted. Patients consented to the publication of the data and images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e: All data is securely stored on a digital database that is password protected. Data is available for review.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePecoraro AJ, Doubell AF. Infective endocarditis in South Africa. Cardiovasc Diagn Ther [Internet]. 2020 Apr [cited 2020 Jun 2];10(2):252\u0026ndash;61. Available from: http://cdt.amegroups.com/article/view/26995/30160\u003c/li\u003e\n\u003cli\u003eHabib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta J-P, Del Zotti F, et al. 2015 ESC Guidelines for the management of infective endocarditis. Eur Heart J [Internet]. 2015 Nov 21;36(44):3075\u0026ndash;128. Available from: https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehv319\u003c/li\u003e\n\u003cli\u003eCahill TJ, Prendergast BD. Current controversies in infective endocarditis. F1000Research [Internet]. 2015 Nov 18;4(0):1287. Available from: http://f1000research.com/articles/4-1287/v1\u003c/li\u003e\n\u003cli\u003eKoegelenberg CFN, Doubell AF, Orth H, Reuter H. Infective endocarditis in the Western Cape Province of South Africa: a three-year prospective study. QJM [Internet]. 2003 Mar 1;96(3):217\u0026ndash;25. Available from: https://academic.oup.com/qjmed/article-lookup/doi/10.1093/qjmed/hcg028\u003c/li\u003e\n\u003cli\u003eKoshy J, Engel M, Human P, Carrara H, Brink J, Zilla P. Long term outcome and EuroSCORE II validation in native valve surgery for active infective endocarditis in a South African cohort. SA Hear. 2018;15(2):116\u0026ndash;26.\u003c/li\u003e\n\u003cli\u003ede Villiers MC, Viljoen CA, Manning K, van der Westhuizen C, Seedat A, Rath M, et al. The changing landscape of infective endocarditis in South Africa. South African Med J. 2019;109(8):592\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eFournier P, Thuny F, Richet H, Lepidi H, Casalta J, Arzouni J, et al. Comprehensive Diagnostic Strategy for Blood Culture\u0026ndash;Negative Endocarditis: A Prospective Study of 819 New Cases. Clin Infect Dis [Internet]. 2010;51(2):131\u0026ndash;40. Available from: https://academic.oup.com/cid/article-lookup/doi/10.1086/653675\u003c/li\u003e\n\u003cli\u003eZamorano J, Sanz J, Moreno R, Almer\u0026iacute;a C, Rodrigo JL, Samedi M, et al. Comparison of outcome in patients with culture-negative versus culture-positive active infective endocarditis. Am J Cardiol [Internet]. 2001 [cited 2020 Nov 4];87(12):1423\u0026ndash;5. Available from: https://www.ajconline.org/action/showPdf?pii=S0002-9149%2801%2901570-3\u003c/li\u003e\n\u003cli\u003eTrichine A, Foudad H, Bouaguel I, Merghit R. 0175: Reassessment of blood culture-negative endocarditis: its profile is similar to that of blood culture-positive endocarditis. Arch Cardiovasc Dis Suppl. 2015;7(1):46\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eLam JC, Fonseca K, Pabbaraju K, Meatherall BL. Case Report: Bartonella quintana Endocarditis Outside of the Europe-African Gradient: Comprehensive Review of Cases within North America. Am J Trop Med Hyg [Internet]. 2019 [cited 2020 Aug 27];100(5):1125\u0026ndash;9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493947/pdf/tpmd180929.pdf\u003c/li\u003e\n\u003cli\u003eEdouard S, Nabet C, Lepidi H, Fournier P-E, Raoult D. Bartonella, a Common Cause of Endocarditis: a Report on 106 Cases and Review. 2015 [cited 2020 Jun 4]; Available from: http://dx.doi.org/10.1128\u003c/li\u003e\n\u003cli\u003eWestern Cape Government. City of Cape Town 2017. 2017; Available from: https://www.westerncape.gov.za/assets/departments/treasury/Documents/Socio-economic-profiles/2017/city_of_cape_town_2017_socio-economic_profile_sep-lg_-_26_january_2018.pdf\u003c/li\u003e\n\u003cli\u003eWharton G, Steeds R, Allen J, Phillips H, Jones R, Kanagala P, et al. A minimum dataset for a standard adult transthoracic echocardiogram: a guideline protocol from the British Society of Echocardiography. Echo Res Pract [Internet]. 2015;2(1):G9\u0026ndash;24. Available from: https://erp.bioscientifica.com/view/journals/echo/2/1/G9.xml\u003c/li\u003e\n\u003cli\u003eWheeler R, Steeds R, Rana B, Wharton G, Smith N, Allen J, et al. A minimum dataset for a standard transoesophageal echocardiogram: a guideline protocol from the British Society of Echocardiography. Echo Res Pract [Internet]. 2015 Dec;2(4):G29\u0026ndash;45. Available from: https://erp.bioscientifica.com/view/journals/echo/2/4/G29.xml\u003c/li\u003e\n\u003cli\u003eMeel R, Essop MR. Striking increase in the incidence of infective endocarditis associated with recreational drug abuse in urban South Africa. South African Med J [Internet]. 2018 Jun 26;108(7):585. Available from: http://www.samj.org.za/index.php/samj/article/view/12330\u003c/li\u003e\n\u003cli\u003eMoodley VM, Zeeman MTS, van Greune CHJ, Corcoran C. Culture-negative endocarditis due to Bartonella quintana. South African Med J [Internet]. 2016 [cited 2020 Aug 27];106(5):470\u0026ndash;1. Available from: http://www.scielo.org.za/pdf/samj/v106n5/29.pdf\u003c/li\u003e\n\u003cli\u003eRaoult D, Fournier PE, Drancourt M, Marrie TJ, Etienne J, Cosserat J, et al. Diagnosis of 22 New Cases of Bartonella Endocarditis. Ann Intern Med [Internet]. 1996 Oct 15 [cited 2020 Sep 18];125(8):646\u0026ndash;52. Available from: http://annals.org/article.aspx?doi=10.7326/0003-4819-125-8-199610150-00004\u003c/li\u003e\n\u003cli\u003ePachirat O, Prathanee S, Watt G. Echocardiographic Features in Bartonella Endocarditis: A Case Series. Cardiol Res [Internet]. 2018 Apr [cited 2020 Aug 27];9(2):116\u0026ndash;9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29755630\u003c/li\u003e\n\u003cli\u003eNakasu A, Ishimine T, Yasumoto H, Tengan T, Mototake H. Infective endocarditis associated with Bartonella henselae: A case series. 2018 [cited 2020 Aug 27]; Available from: https://doi.org/10.1016/j.idcr.2018.04.011\u003c/li\u003e\n\u003cli\u003eBartonella Serology interpretation [Internet]. [cited 2020 Nov 10]. Available from: https://www.childrensmn.org/references/Lab/serology/bartonella-antibody.pdf\u003c/li\u003e\n\u003cli\u003eGhidey FY, Igbinosa O, Mills K, Lai L, Woods C, Ruiz ME, et al. Case Series Case series of Bartonella quintana blood culture-negative endocarditis in Washington, DC. [cited 2020 Aug 27]; Available from: http://jmmcr.microbiologyresearch.org\u003c/li\u003e\n\u003cli\u003eFournier P-E, Gouriet F, Casalta J-P, Lepidi H, Chaudet H, Thuny F, et al. Blood culture-negative endocarditis Improving the diagnostic yield using new diagnostic tools. 2017 [cited 2020 Nov 4]; Available from: http://dx.doi.org/10.1097/MD.0000000000008392\u003c/li\u003e\n\u003cli\u003eSilverman ME, Upshaw CB. Extracardiac Manifestations of Infective Endocarditis and Their Historical Descriptions. Am J Cardiol [Internet]. 2007 [cited 2020 Sep 23];100:1801\u0026ndash;7. Available from: www.AJConline.org\u003c/li\u003e\n\u003cli\u003eBerdejo J, Shibayama K, Harada K, Tanaka J, Mihara H, Gurudevan S V., et al. Evaluation of vegetation size and its relationship with embolism in infective endocarditis: A real-time 3-dimensional transesophageal echocardiography study. Circ Cardiovasc Imaging. 2014;7(1):149\u0026ndash;54.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u0026nbsp;Table 1.\u0026nbsp; Demographic information, clinical and imaging findings\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u003cstrong\u003eDemographic information\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eAge (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eRural/Urban\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eRural\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eUrban\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eUrban\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eRural\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eUrban\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eRural\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eHousing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eInformal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eFormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eHomeless\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eFormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eFormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eInformal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003e\u003cstrong\u003eClinical and imaging features\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eClubbing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eAnemia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eHematuria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eValve involvement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMitral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eHemodynamic lesion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAcute\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAcute on chronic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAcute on chronic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eChronic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAcute\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eAcute on chronic\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eVegetation length (mm)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eVegetation circumference (mm)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003eVegetation number\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMultiple\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMultiple\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eSingle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMultiple\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMultiple\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eMultiple\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"191\"\u003e\n\u003cp\u003ePre-existing valvular structure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"75\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp; Special investigations and surgical outcome\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003eSpecial investigations\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003eB. quintana\u003c/em\u003e IgG\u003c/p\u003e\n\u003cp\u003eTitre\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003eB. quintana\u003c/em\u003e IgM\u003c/p\u003e\n\u003cp\u003eTitre\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:128\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003eB. henselae\u003c/em\u003e IgG\u003c/p\u003e\n\u003cp\u003eTitre\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:256\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cem\u003eB. henselae\u003c/em\u003e IgM\u003c/p\u003e\n\u003cp\u003eTitre\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:512\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003cp\u003e1:128\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e16S PCR on valve tissue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cem\u003eB. quintana\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNot done\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cem\u003eB. quintana\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cem\u003eB. quintana\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e\u003cem\u003eB. quintana\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e16S PCR on blood cultures\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHIV status\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003ePositive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNegative\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e209\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eWCC (per microliter)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e7700\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e10000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e27600\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e7300\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e3150\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e8800\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eComplement level\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNormal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003eValve replaced\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eRefused\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eMitral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eAortic\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003eIn-hospital mortality\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent follow-up period (days)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e369\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e128\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e352\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e306\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e226\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"79\"\u003e\n\u003cp\u003e130\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcm","sideBox":"Learn more about [European Journal of Clinical Microbiology \u0026 Infectious Diseases](https://www.springer.com/journal/10096)","snPcode":"10096","submissionUrl":"https://submission.nature.com/new-submission/10096/3","title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Infective endocarditis, blood culture negative endocarditis, Bartonella quintana, Bartonella henselae","lastPublishedDoi":"10.21203/rs.3.rs-230749/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-230749/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: \u003c/p\u003e\u003cp\u003ePrevious reports have highlighted the high prevalence of blood culture negative endocarditis (BCNE) in South Africa.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\u003cp\u003eThe Tygerberg Endocarditis cohort (TEC) study is a prospective cohort study of patients with confirmed or suspected IE presenting to Tygerberg Academic Hospital, Cape Town, South Africa. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003eTo date, 44 patients have been included in this ongoing study.\u0026nbsp;Fourteen of the 44 patients (31.8%) had BCNE. Further analysis of the patients with BCNE identified \u003cem\u003eBartonella \u003c/em\u003especies as the most common causative organism (n=6; 43%). Other causes included \u003cem\u003eMycoplasma \u003c/em\u003especies (n=2), \u003cem\u003eC. burnetii\u003c/em\u003e (n=1), and non-bacterial thrombotic endocarditis due to anti-phospholipid syndrome (n=1).\u0026nbsp;No cause could be identified in 4 of the 44 patients (9%).\u0026nbsp;\u003cem\u003eBartonella quintana\u003c/em\u003e was identified with PCR of valvular tissue as the causative organism in 4 of the 5 patients that underwent urgent surgery. \u003c/p\u003e\u003cp\u003eThe patients with Bartonella\u003cem\u003e \u003c/em\u003eIE (n=6) had an average age of 39 years with equal gender distribution The common clinical features were clubbing (n=5; 83%), anemia (n=4; 66.6%), haematuria (n=3; 50%), acute on chronic severe valvular lesion (n=3; 50%) and acute severe valvular lesion (n=2; 33.3%). \u003c/p\u003e\u003cp\u003eThe aortic valve was involved in 5 of 6 patients.\u0026nbsp;During a mean follow-up period of 251 days after diagnosis, no major adverse events occurred.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003eBartonella IE is an important cause of BCNE in the Western Cape of South Africa.\u0026nbsp;\u0026nbsp;\u0026nbsp;Imaging findings of significant valvular destruction with large vegetations on the aortic valve not affected by pre-existing congenital or rheumatic valve disease, should raise the suspicion of Bartonella IE.\u0026nbsp;\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Bartonella Species as a Cause of Culture-negative Endocarditis in South Africa\u0026nbsp;","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-15 16:34:23","doi":"10.21203/rs.3.rs-230749/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-02-15T00:00:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-02-10T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","date":"2021-01-14T00:06:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcm","sideBox":"Learn more about [European Journal of Clinical Microbiology \u0026 Infectious Diseases](https://www.springer.com/journal/10096)","snPcode":"10096","submissionUrl":"https://submission.nature.com/new-submission/10096/3","title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4d0fe6a8-3538-438d-9102-c5e3cba58628","owner":[],"postedDate":"February 15th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":2409514,"name":"General Microbiology"},{"id":2409515,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2021-08-18T19:35:13+00:00","versionOfRecord":{"articleIdentity":"rs-230749","link":"https://doi.org/10.1007/s10096-021-04239-w","journal":{"identity":"european-journal-of-clinical-microbiology-and-infectious-diseases","isVorOnly":false,"title":"European Journal of Clinical Microbiology \u0026 Infectious Diseases"},"publishedOn":"2021-04-07 19:07:05","publishedOnDateReadable":"April 7th, 2021"},"versionCreatedAt":"2021-02-15 16:34:23","video":"","vorDoi":"10.1007/s10096-021-04239-w","vorDoiUrl":"https://doi.org/10.1007/s10096-021-04239-w","workflowStages":[]},"version":"v1","identity":"rs-230749","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-230749","identity":"rs-230749","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}