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International Journal of Cardiology 167 (2013) 640645

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International Journal of Cardiology


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Review

Tuberculous Endocarditis
Alexander Liu a, Edward Nicol a, Yanmin Hu b, Anthony Coates b,
a
National Heart and Lung Institute, Imperial College London, United Kingdom
b
Division of Clinical Sciences, St George's University London, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Mycobacterium tuberculosis (TB) is a major cause of death globally. TB is capable of infecting every organ in
Received 31 May 2012 the body, and the heart is no exception. Tuberculous endocarditis (TBE) was rst reported in 1892 and sub-
Received in revised form 11 July 2012 sequently many other cases have been described, highlighting the signicant morbidity and mortality asso-
Accepted 21 August 2012
ciated with this manifestation of TB. TBE usually presents with miliary tuberculosis and most early cases
Available online 26 September 2012
were diagnosed on autopsy. With increasing application of prosthetic valve replacements in the treatment
Keywords:
of infective endocarditis (IE), TB infections have begun to affect these as well as native valves. With the intro-
Mycobacterium tuberculosis duction of TB culture methods and drug therapy, the prognosis has improved. HIV and drug resistance are
Tuberculosis likely to make the management of TBE more difcult in the future. Large scale studies, both prospective
Tuberculous and retrospective, are required to ascertain the true incidence of TBE whilst development of novel anti-TB
Endocarditis therapy is also required to combat resistance. We present the rst extensive literature review on TBE in over
75 years.
Crown Copyright 2012 Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction in the body [7]. Tuberculous endocarditis (TBE) has not been reviewed
in the medical literature since 1935.
Mycobacterium tuberculosis (TB) kills nearly 4700 people daily [1]. We performed a literature search of MEDLINE using criteria
It is most lethal in the developing world but is re-emerging in Europe containing tuberculous endocarditis, tuberculosis endocarditis,
and North America, in part due to the emergence of multiple drug re- TB endocarditis, valvular tuberculosis, endocardial tuberculosis,
sistance and co-infection with human immunodeciency virus (HIV) endocardial tuberculous, endocardial TB. All relevant articles and
[1]. Many of the difculties in managing TB reside in its complex the references were reviewed with exclusion of animal studies. We
pathogenesis, particularly its persistence despite treatment, which re- obtained permission and consent for the use of patient material. We
mains incompletely understood. aim to summarise the evidence for TBE to reect the evolution of diag-
TB is an acid-fast bacillus (AFB) transmitted by aerosol. In clinical nostics, treatment and future challenges in this cardiovascular manifes-
practice, rapid diagnosis, case-nding and directly observed treatment tation of the most prevalent infectious disease in the world.
short-course (DOTS) therapy are effective measures of disease control
[2]. Problems arise however when these measures are unavailable, 2. The golden age of pioneering discovery
poorly delivered or patient compliance is low. Once inhaled, AFB are
engulfed by alveolar macrophages and dendritic cells [3]. Rather than Giant cells and caseating granulomas were the benchmark features
perishing, like most other bacteria, TB persists in these metabolically used to diagnose TBE at the turn of the 20th century [8]. However, with-
hostile environments, leading to further phagocytic chemotaxis [3]. out positive culture conrmation, these histological ndings were high-
Meanwhile, antigen presentation by dendritic cells results in the inux ly suggestive of TBE rather than diagnostic. The spread of tuberculosis in
of lymphocytes to the site of infection. Macrophage activation by lym- endocarditis is likely to be haematological, and as early as 1903, Braillon
phocytes leads to the partial destruction of the AFB with granuloma for- and Jousset described a patient in whom tubercle bacilli were isolated
mation [3]. Over time, these foci of inammatory cells undergo central both from venous samples during life and from valvular vegetations
caseation and a proportion of bacilli remains dormant only to reactivate on autopsy. They claimed to have reported a case of primary TBE, how-
leading to miliary disease [3]. ever failure to specify the presence or absence of hepatic and splenic TB
TB is known to affect the pericardium [4], myocardium [5] and val- meant that such a conclusion was contentious [9,10].
vular structures of the heart[6] as well as virtually every other organ In 1899, Marshall and Benda specied that TBE could only be diag-
nosed if tubercle bacilli were found deep within valvular vegetations
located above the elastica [1012]. Bacilli found supercially may occur
Corresponding author. Tel.: +44 2087255725; fax: +44 2087250137. due to accidental contamination and lesions found below the elastica
E-mail address: acoates@sgul.ac.uk (A. Coates). are more indicative of myocarditis [10]. Clinically, the vast majority of

0167-5273/$ see front matter. Crown Copyright 2012 Published by Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijcard.2012.08.009
A. Liu et al. / International Journal of Cardiology 167 (2013) 640645 641

TBE cases were accompanied by miliary disease, with dismal prognosis TBE [27]. Of note, the valvular vegetation was missed on transthoracic
[1214]. Patients presented with non-specic symptoms of miliary TB echocardiography and supports the argument that endocarditis (of any
rather than characteristic features of infective endocarditis [10]. Meek cause) remains a clinical diagnosis. Sogabe et al. present a 63 year old
described two patients with symptoms of haemoptysis and abdominal man with acute aortic insufciency and a sub-aortic valve aneurysm
discomfort, however at autopsy, orid evidence of TB was observed who underwent aortic valve replacement. Histology suggested TBE, how-
deep within the aortic and mitral vegetations of the rst patient, ever AFB were not detected in either blood cultures or surgical specimens
while bacilli were sparsely distributed in the mitral lesions of the [28]. Recently, Sultan et al. described a 30 years old man with tuberculous
second [10]. No other micro-organisms were isolated [10]. Only the involvement of the mitral valve and right atrium who underwent MVR
rst case was regarded as true TBE as the second failed to satisfy Marshall [6]. TB was cultured from the excised valve 20 days post-operatively.
and Benda's diagnostic criteria. He received anti-TB chemotherapy for 10 months leading to resolution
of disease [6]. Of note, anti-TB chemotherapy is considered adjuvant to
3. 1935 to 1950 A renaissance of ideas surgery and facilitated disease eradication.
Having noted a case where echocardiography missed the vegeta-
In 1935, Baker reviewed 30 cases of TBE, of which only 5 satised tion, we illustrate two cases of suspected TBE in whom transthoracic
his upgraded diagnostic criteria: 1) microscopic evidence of tuberculous echocardiogram (TTE) images were diagnostic (Fig. 3). The rst patient
reaction; 2) positive tubercle bacilli staining; 3) exclusion of other causes was a male intravenous drug user who presented in cardiogenic shock
of endocardial lesions. The presence of tubercle bacilli in the blood stream (Fig. 3A). His TTE images demonstrated tricuspid valve endocarditis
or miliary TB, in isolation, is insufcient to diagnose TBE [10,12,14,15]. In and he subsequently underwent tricuspid valve replacement. Tissue
the same period, Beare described 16 patients with cardiac tuberculosis culture of the resected valve failed to demonstrate evidence of tubercu-
from a cohort of 3,500 cadavers. Of these, only one case demonstrated losis. The second patient had a history of prolonged prostration and
Ziehl-Neelsen (ZN) positive valvular involvement (0.03%) [16]. In a sim- weight loss and also presented in cardiogenic shock. TTE images dem-
ilar autopsy study of 900 patients with TB, Baker found 6 cases of TBE onstrate an aortic valve vegetation (Fig. 3B). Once again tissue culture
(0.67%) [15]. Notably, miliary tuberculosis co-existed with every case of the resected aortic valve did not show evidence of tuberculosis, how-
described [17,18]. ever gram positive rods were found in blood cultures of both patients. In
Extensive TBE has a predilection for the systemic circulation and may both these cases, TTE provided early indications of endocarditis without
affect multiple valves [10,19,20]. In 1936, Davie described a 24 years old specically diagnosing TBE. Serial blood cultures remain key to provid-
female with systemic TB in whom AFB were detected in aortic and mitral ing the denitive diagnosis.
valve vegetations. Similarly, Bevan and Wilkins reported a 17 year old
male with dyspnoea, arthralgia and heart block in whom inammatory 5. Prosthetic valve TBE
inltrates and AFB were found in aortic and mitral lesions [19,20].
Haematological deposition of bacilli leading to right sided TBE Surgical management of TBE involves replacement with either
usually affects the pulmonary valves [21,22]. Gilmore et al. isolated AFB metallic or porcine valves. allowing the treatment of the original valvu-
from vegetations on the right anterior cusp of the pulmonary valve in a lar defect as well as extraction of the diseased tissue for TB culture [6].
21 years old man with extensive systemic tuberculosis and proposed Positive cultures enable commencement of appropriate anti-TB chemo-
that TB was seeded via a plexus of blood vessels at the base of the valvu- therapy maximising the likelihood of TB eradication [6]. This is ex-
lar cusp [22]. The true mechanism of the origins of tuberculous vegeta- tremely important as empirical antibiotics have limited action against
tions remains largely hypothetical. TB.
Despite obvious benets of surgical management, TB may also affect
4. Modern era of antibiotics, immunosuppression and valve surgery valvular prostheses, albeit in b 1% of cases.[29] Porcine valves and ho-
mografts are predominantly affected. Implantation of contaminated ho-
The discovery and widespread use of anti-tuberculous antibiotics mografts has led to miliary tuberculosis in recipients. In 1979, Anyanwu
caused a paradigm shift in the management of TB. Remission from et al. analysed a pool of over 800 homograft recipients and demonstrat-
TBE was rst reported in 1981 by Soyer et al. in a 20 year old woman ed seven cases of miliary TB post operatively [29]. This alarming rate of
with severe aortic insufciency secondary to aortic annulus erosion by homograft infections was attributed to post-mortem contamination
an endocardial tuberculoma [23]. She underwent aortic valve replace- and a lack of antibiotics treatment in the processing of extracted valves.
ment and anti-TB chemotherapy [23]. Pharmacological management More recent studies demonstrate much lower rates of miliary TB in
alone has produced mixed results in patients with TBE, notably, many
patients still succumbed to miliary tuberculosis [24,25].
Individuals with tuberculosis and HIV co-infections have worsened
prognoses since immunosuppression renders these patients vulnerable
to the development of miliary tuberculosis. In 2002, Fumagalli reported
TBE in a 35 years old intravenous drug user (IVDU) with poorly treated
HIV infection [26]. Blood cultures were positive for TB and trans-
thoracic echocardiography (TTE) demonstrated tricuspid valve vegeta-
tions, which resolved following chemotherapy with rifampicin, isoniazid,
pyrazinamide and ethambutol [26]. The authors encouraged the consid-
eration of TB as a differential diagnosis of valvular disease in HIV patients
[26]. This report showed that tricuspid valve endocarditis can result from
TB as well as conventional bacteria such as Staphylococcus aureus in IVDU.
Three cases of TBE without systemic involvement, in immune-
competent patients, have been described. In all cases, valve replace-
ment accompanied by anti-TB drugs formed the cornerstones in manage-
ment [6,27,28]. Klingler et al. describe a 64 years old man with severe
mitral regurgitation who was cured with a mitral valve replacement
(MVR) and anti-TB drugs. Histology of the excised tissue valve demon- Fig. 1. Summary of the available management of tuberculous endocarditis through
strated calcied granulomas and culture of the vegetation conrmed time. TB denotes Mycobacterium tuberculosis.
642 A. Liu et al. / International Journal of Cardiology 167 (2013) 640645

partly improved specicity at the cost of potentially overlooking impor-


tant cases [15].
Obtaining reliable diagnosis from clinical features alone was dif-
cult due to the concurrence with miliary TB, which presented with
non-specic symptoms [10]. Interestingly, early reports rarely de-
scribed clinical features characteristic of valvular disease. Instead,
most patients presented with constitutional symptoms indicative of
systemic tuberculosis [22]. Fever was the most frequently reported
complaint [6]. Unexplained weight-loss and lethargy were also com-
mon [22]. Symptoms of pulmonary TB such as cough and haemoptysis,
although commonly described one hundred years ago, did not feature
in recent cases [6,10,27].
TBE rarely presents with signs and symptoms of other cardiovascu-
Fig. 2. Ziehl-Neelsen (ZN) staining of tubercle bacilli. This image from our laboratory lar diseases, such as pericarditis or myocarditis, unless there was con-
demonstrates dark purple stained tuberculous bacilli on a background of pink stained current involvement [6,19,27]. The case of TBE described by Bevans
macrophages. and Wilkins demonstrated myocardial and interventricular septal bro-
sis. Such extensive cardiac damage would have accounted for the con-
recipients whilst the most recent analysis of 27,840 valves failed to duction defect (heart block) and exercised induced palpitations, which
identify a single case of TB contamination [3032]. This is largely due the patient experienced [19]. Currently, substantial association data be-
to the exclusion of at-risk donors which is a superior method compared tween TBE and pericarditis or aortic mycotic aneurysms are lacking.
to graft screening with AFB stains. When related to valvular dysfunction, patients presented with symp-
In 1979, Wainwright described the rst cases of TBE on a mitral toms indicative of cardio-pulmonary failure, e.g. dyspnoea and reduced
valve prosthesis in a 28 year old lady with heart failure and pulmonary exercise tolerance [6,19].
hypertension [33]. She underwent an MVR of a calcied and stenosed In 2008, the WHO estimated the case detection rate of sputum-
mitral valve. Five months later, she presented with non-specic symp- positive TB to be 61% [1]. However, TBE does not always manifest
toms of chest pain, backache, loss of appetite and diarrhoea [33]. At with pulmonary involvement meaning sputum analysis alone is un-
autopsy, miliary TB was diagnosed with isolation of AFB from the mitral likely to yield a high specicity for TBE [9]. No study to date has investi-
valve prosthesis. Her rapid clinical deterioration meant that the diagnosis gated valvular manifestations in patients with pulmonary tuberculosis.
was not suspected prior to death. A decade later, Yamane et al. reported Indeed, miliary TB, rather than pulmonary, is more intimately associated
two fatal cases of miliary TB after aortic xenograft endocarditis. Neither with endocarditis. This adds weight to the hypothesis that TB is deposited
patients survived beyond one year [34]. onto valves haematologically [9].
Although post-operative survival following TBE is considered to be Advances in TB treatment have led to improved prognosis with the
excellent, there is a lack of data on long term follow-up, due to the clinical goal now being curative, upon early diagnosis. Two major de-
relatively infrequent occurrence of valvular tuberculosis. TB may be- velopments have transformed TBE diagnosis; rstly the ability to de-
come dormant and reactivate later causing endocarditis and miliary tect TB from diseased valves after surgery and secondly the use of
disease [33]. Since TBE commonly occurs with systemic involvement, echocardiography.
it is important to know the rate of valvular infection upon reactivation.
Table 1 summarises the signicant cases of TBE. 7. Tissue detection of TB

6. The evolution TBE diagnosis The widespread use of AFB staining (Fig. 2) and TB cultures has
undoubtedly increased diagnostic accuracy. However, there is cur-
TBE diagnostics evolved greatly since the 1900s with a shift from rently no single assay, which offers 100% predictive value for the diag-
histological observations made on autopsy to post-operative tissue nosis of TB [35]. The cases reported have relied on best evidence
cultures from the living (summarised in Fig. 1). An early reliance on obtained from diagnostic methods employed for pulmonary TB [35].
histological diagnosis led to the development of stringent criteria which Ziehl-Neelsen (ZN) staining has a sensitivity of 50%-80% whilst that

A B

Fig. 3. Trans-thoracic Echocardiograms (TTE) images of suspected tuberculous endocarditis. A) apical four chamber view demonstrating a tricuspid valve vegetation in a male
intravenous drug user (arrow). B) parasternal long axis view demonstrating an aortic valve vegetation in a man with a history of prostration and weight loss (arrow).
A. Liu et al. / International Journal of Cardiology 167 (2013) 640645 643

Table 1
Signicant reports of tuberculous endocarditis.

Authors Year Method of TB diagnosis Precise Valvular Involvement Extra-cardiac involvement Management

Burkhardt [8] 1892 Histology Mitral Miliary disease Supportive


Benda [12] 1899 Histology Mitral Miliary disease Supportive
Braillon and Jousset [9] 1903 Histology Mitral Miliary disease Supportive
Witte [14] 1904 Histology Mitral Miliary disease Supportive
Sorgo and Suez [47] 1906 Histology Unspecied Miliary disease Supportive
Meek [10] 1908 Histology Aortic and Mitral Miliary disease Supportive
Reinhard [13] 1912 Histology Unspecied Miliary disease Supportive
Baker [15] 1935 Histology Aortic and Mitral Miliary disease Supportive
Marchiafava [15] 1935 Histology Unspecied Miliary disease Supportive
Davie [20] 1936 AF staining Aortic and Mitral Miliary disease Supportive
Mark [21] 1938 Histology Pulmonary Miliary disease Supportive
Ward [17] 1938 Histology Mitral Miliary disease Supportive
Gilmore [22] 1940 AF staining Pulmonary Miliary disease Supportive
Bevan and Wilkins [19] 1942 AF staining Aortic and Mitral Miliary disaese Supportive
Egidio [18] 1944 AF staining Aortic Miliary disease Supportive
Beare [16] 1947 AF staining Mitral Miliary disease Supportive
Anyanwu [29] 1976 AF staining / TB cultures Aortic and Mitral Miliary disease Anti-TB drugs (unspecied length)
Wainwright [33] 1979 AF staining Mitral Miliary disease Supportive
Yamane [34] 1989 TB cultures Mitral Miliary disease Supportive
Klingler [27] 1998 AF staining / TB cultures Mitral Unspecied VR / Anti-TB drugs (12 months)
Soyer[23] 1981 AF Staining Aortic Unspecied VR / Anti-TB drugs (12 months)
Kannangara[25] 1984 AF Staining Mitral Unspecied Supportive
Cope[24] 1990 AF Staining Aortic Miliary disease VR / Anti-TB drugs (12 months)
Fumagalli [26] 2002 TB cultures Tricuspid Miliary disease with HIV VR / Anti-TB drugs (6 months)
Sogabe [28] 2007 Histology Aortic Unspecied VR / Anti-TB drugs (9 months)
Sultan [6] 2010 TB cultures Mitral Unspecied VR / Anti-TB drugs (12 months)

Keys: TB denotes Mycobacterium tuberculosis; AF, Acid-fast; HIV, Human Immunodeciency Virus; VR, surgical valve replacement of the diseased valve.

Anti-TB drugs typically consists of quadruple chemotherapy (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) for 2 months, followed by duel therapy (Rifampicin and Isoniazid) for
the rest of the duration.

of blood culture is approximately 98% [36,37]. However, positively It is important to note that whilst the demonstration of vegetations or
stained bacilli are not always isolated and TB cultures take a valvular dysfunction is suggestive of TBE, the nding is neither sensitive
long time to complete [6,28]. Three main types of culture media are nor specic. Denitive diagnosis, as with all forms of infective endocardi-
available; egg-based Lowenstein-Jensen; agar-based Middlebrook tis, relies on a constellation of clinical assessment, blood tests, imaging
7 H10 or 7 H11; and liquid-based Middlebrook 7 H12. Among these, and tissue cultures [6]. When the diagnosis of TBE is in doubt, more com-
liquid-based media facilitate the fastest growth of TB, with detection mon causes of infective endocarditis need to be excluded [43]. The Duke
within 13 weeks [38]. Of the solid media, AFB grows faster on Criteria necessitates the drawing of blood, which should be tested for
agar-based variants.[39] Newer automated liquid-based culture sys- bacterial microscopy, culture and sensitivity including TB [43]. Positive
tems, such as BACTEC 460 TB, offer the fastest rate of TB growth and echocardiographic ndings of valvular vegetation and positive TB cul-
are more sensitive than other currently available solid media [39]. Un- tures in a patient presenting with clinical signs of endocarditis would
fortunately, reports of TBE in the literature have not specied the sufce as diagnosis of TBE [6,27,28].
types of culture media used.
Polymerase chain reaction (PCR) can be used to amplify TB DNA 9. 21st Century management of TBE
fragments [35]. It delivers a high detection rate, and requires only a
few base pairs of TB genome for diagnosis [5]. Real-Time-PCR (rtPCR), Historically, TBE was diagnosed at autopsy and tissue conrmation
which detects RNA fragments reecting tuberculous gene expression, yielded little more than research data, conveying no treatment benets
have a sensitivity and specicity of 98% and 99%, respectively.[40] TB [19]. The management of TBE was purely supportive and the develop-
PCR has been successfully employed in the diagnosis of tuberculous ment of miliary disease with rapid clinical deterioration was almost in-
myocarditis, however its use has not been reported in TBE [5,41]. evitable in the pre-antibiotics era [10]. TBE remains a relatively rare
phenomenon despite its early discovery, therefore large randomised
8. Cardiovascular imaging controlled trials on management, follow up and pharmacology are lack-
ing. Treatment still relies on evidence derived from pulmonary or mili-
Echocardiography is the rst line imaging tool performed for all ary TB, with the assumption that the same chemotherapy is effective
cases of suspected infective endocarditis and has provided pivotal infor- against TBE. Fig. 1 summarises the management of TBE over time.
mation in every case of TBE since 1980 [6,42]. However, trans-thoracic The modern management of TBE involves surgical replacement of
echocardiography (TTE) is less invasive than trans-esophageal echocar- damaged valves and aggressive disease eradication with anti-TB chemo-
diography (TEE) but is inferior in terms of spatial resolution and perfor- therapy [6]. Diagnosis relies on a high index of suspicion, especially in pa-
mance in obese patients or those with respiratory pathology [42]. TTE is tients who are prone to miliary disease, namely the immunosuppressed
performed if the quality of imaging is likely to be good [42] and the and patients presenting with orid constitutional symptoms.[39] TBE is
majority of recent patients presented in this paper underwent TTE not infectious unless complicated with symptomatic pulmonary disease
without TEE. In patients with culture positive valves post replacement, and isolation may be stopped once respiratory symptoms cease [39]. Pos-
pre-operative TTE often fails to detect endocardial vegetations, despite itive blood or tissue cultures necessitate the commencement of anti-TB
adequate assessment of valvular function [27,28]. It is likely that these drug treatments [6].
lesions were too small to be detectable trans-thoracically. There is no Despite signicant advances in tissue based diagnostics and cardiac
published data on the use of TEE in the assessment of tuberculous endo- imaging techniques, the major difculty in TBE management lies in
carditis and there are no studies comparing the diagnostic accuracy of making timely diagnosis. Due to the differences in antibiotic manage-
the two modalities of echocardiography. ment between TBE (prolonged quadruple therapy) and conventional
644 A. Liu et al. / International Journal of Cardiology 167 (2013) 640645

infective endocarditis (e.g. penicillin /aminoglycosides), there is a justi- and YH are also grateful for nancial support from Helperby Therapeu-
ed clinical reluctance in commencing anti-tuberculous chemotherapy tics Group Ltd. AC and YH are shareholders in Helperby, and AC is a
until a diagnosis of TBE is conrmed, or at least highly suspected [6]. In director.
the clinical setting, patients would not have been taking anti-TB drugs
upon presentation and further delays in establishing the diagnosis
would allow the disease to progress to an advanced stage. Therefore, re- Disclosures
ducing the door-to-treatment time, which can take weeks in some
cases, is likely to lead to improved TBE management. None.
The delay in diagnosis is compounded by a failure of TTE to detect
certain TBE vegetations. Much like conventional infective endocardi-
Acknowledgement
tis, valvular vegetations in TBE occur in variable sizes. According to
autopsy studies these vegetations range from a few millimetres to a
The authors of this manuscript have certied that they comply
few centimetres [10,20,27]. The physiological factors which govern
with the Principles of Ethical Publishing in the International Journal
this are unclear. Clinically, the majority of the vegetations were large
of Cardiology.
enough to cause haemodynamic compromise [6,10,27]. There appears
to be little correlation between the sizes of TBE vegetations in immuno-
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