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.