Challenges in Infective Endocarditis

Thomas J. Cahill, MBBS; Larry M. Baddour, MD; Gilbert Habib, MD; Bruno Hoen, MD, PHD; Erwan Salaun, MD; Gosta B. Pettersson, MD, PHD; Hans Joachim Schäfers, MD; Bernard D. Prendergast, DM

Disclosures

J Am Coll Cardiol. 2017;69(3):325-344. 

In This Article

Diagnosis

Reaching a rapid and accurate diagnosis in cases of suspected IE is a central challenge of the disease. Delayed diagnosis and initiation of therapy lead to complications and worse clinical outcomes.[56–58] Clinical presentation is notoriously diverse, ranging from acute sepsis to an indolent low-grade febrile illness, a heart failure syndrome, or stroke. Furthermore, the modified Duke criteria, originally designed for research purposes and advocated by AHA guidelines for evaluation of patients with suspected IE, have a lower sensitivity for patients with prosthetic valve endocarditis (PVE) or cardiac device infection (CDI).[59,60] Up to 30% of patients with subsequently proven IE are labeled as "possible" due to equivocal or negative findings on echocardiography or blood cultures.[61,62] Definitive cardiac imaging and microbiology are therefore of integral importance in making the diagnosis and also inform risk stratification, direct management, identify complications, and assist with monitoring therapy. Key advances have been made in recent years in reaching a definitive diagnosis in patients who fall into the "possible" group according to the Duke criteria.

Imaging

Echocardiography remains the cornerstone of imaging and is rapid, straightforward, and, in many cases, diagnostic.[63] Transthoracic echocardiography (TTE) is the recommended initial modality of choice for both native valve infective endocarditis (NVE) and PVE. For suspected NVE, TTE has a sensitivity of 50% to 90% and a specificity of 90%. For suspected PVE, the sensitivity of TTE is lower, at 40% to 70%, yet it provides value in assessment of ventricular size and function, hemodynamic severity of valve lesions, and in the diagnosis of anterior prosthetic aortic valve abscesses, which may be difficult to visualize on transesophageal echocardiography (TEE). TEE is indicated when TTE is positive or nondiagnostic, when complications are suspected, or when intracardiac device leads are present. For suspected NVE, TEE has a sensitivity of 90% to 100% and a specificity of 90% for detection of vegetations, and it is superior to TTE for detection of complications, such as perforations, abscesses, and fistulae. In PVE, a recent meta-analysis reported a pooled sensitivity of only 86% (95% confidence interval [CI]: 77% to 92%) for TEE in making the diagnosis,[64] and other imaging modalities are emerging to help make or exclude the diagnosis in cases in which TEE is nondiagnostic. Even when abnormalities are detected, it can be difficult to differentiate nodules from small vegetations or distinguish signs of infection from post-operative changes.

Cardiac computed tomography (CT) scanning is the key adjunctive modality for use when the anatomy is not clearly delineated according to echocardiography, and it now has a Class II, Level of Evidence: B recommendation for use in IE in the 2014 ACC/AHA valvular heart disease guidelines (Figure 1).[59] Cardiac CT is equivalent (and possibly superior) to TEE for demonstrating paravalvular anatomy and complications (e.g., paravalvular abscesses or mycotic aneurysms) and is subject to fewer prosthetic valve artifacts than echocardiography.[65–67] This approach may help with planning surgical strategy, and concurrent CT angiography allows exclusion of significant coronary disease in younger patients. Detection of paravalvular lesions by using CT imaging is now a major diagnostic criterion in the 2015 ESC guidelines on IE.[68]

Figure 1.

Cardiac CT in IE
A 78-year-old man was admitted with infective endocarditis (IE) on an aortic bioprosthesis. Blood culture specimens were positive for Enterococcus faecalis. Initial transthoracic echocardiography imaging demonstrated a suspected anterior and intercoronary pseudoaneurysm on parasternal long-axis (A) and short-axis (B) views (arrows). On transesophageal echocardiography (C and D), a vegetation (C, red arrow) and pseudoaneurysm (D, white arrow) were visualized, although the insertion of the vegetation was not apparent due to shadowing from the frame of the bioprosthesis. On cardiac computed tomography (CT) scanning, the vegetation was seen in the left ventricular outflow tract view (E, red arrow), which also demonstrated the insertion of the vegetation on the anterior leaflet. The short-axis cardiac CT view (F) confirmed the anterior pseudoaneurysm and 3-dimensional reconstruction (G) allowed delineation of the position of the pseudoaneurysm relative to the coronary arteries. AO = aorta; LA = left atrium; LV = left ventricle; RV = right ventricle.

Combining CT imaging with metabolic imaging by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) or leukocyte scintigraphy (radiolabeled leukocyte single-photon emission computed tomography [SPECT]) to show regions of metabolic activity or inflammation, respectively, is a hugely promising approach in patients who, according to the Duke criteria, have "possible" IE or suspected CDI (Figure 2). Several studies have now investigated the sensitivity and specificity of PET/CT or SPECT/CT imaging in this setting. In a cohort of 72 patients with suspected PVE, 18FDG PET/CT imaging had an overall sensitivity of 73% and a specificity of 80%.[69] The addition of "abnormal prosthetic valve 18FDG-PET signal" as a diagnostic criterion increased the sensitivity of the modified Duke criteria from 70% to 95%, reducing the number of patients with "possible IE" from 56% to 32%. In a Spanish cohort of patients with suspected PVE or CDI, 18FDG-PET/CT (angiography) demonstrated an overall sensitivity and specificity of 87% and 90%, respectively, and increased the sensitivity of the modified Duke criteria from 51% to 91%.[70] Use of PET/CT imaging allowed reclassification of 90% of cases (35 of 39) with "possible" IE and provided a conclusive diagnosis in 95% of cases overall. For leukocyte scintigraphy with SPECT/CT imaging, a sensitivity of 90% and a specificity of 100% have also been reported.[71] When directly compared in a cohort with suspected PVE and inconclusive echocardiography findings, 18FDG-PET/CT imaging had higher sensitivity than SPECT/CT imaging, but SPECT demonstrated higher specificity.[72] The significance of abnormal 18FDG-PET/SPECT imaging has been recognized in the 2015 ESC guidelines; a positive signal at the site of a prosthetic valve (if implanted >3 months previously) is now regarded as a major diagnostic criterion for PVE.

Figure 2.

Integrated Imaging Strategy in Patients With Suspected IE
(A) Integrated imaging strategy in patients with suspected infective endocarditis (IE). In the challenging subgroup of patients with possible IE after initial evaluation by transthoracic echocardiography and transesophageal echocardiography (TEE), cardiac CT imaging, metabolic imaging, or cross-sectional imaging of the head and viscera by CT scanning or magnetic resonance imaging (MRI) may help to reach an early definite diagnosis. Panels B to F: 18-Fluorodeoxyglucose positron emission tomography (18FDG-PET/CT) imaging for diagnosis. A 54-year-old woman with a history of mitral valve replacement 5 years previously was admitted with features of acute left ventricular failure. Transthoracic echocardiography on admission revealed severe intraprosthetic regurgitation. The TEE bicommissural (B and C) and 3-dimensional atrial (D) views revealed a leaflet perforation (arrow) and severe regurgitation but no evidence of vegetation. Blood cultures on admission were negative, although inflammatory markers were raised. Antibiotics for suspected blood culture-negative IE were started, and 18FDG-PET/CT imaging confirmed the diagnosis with focal signal uptake on the mitral bioprosthesis (E and F, red arrow). Panels G to K: Cross-sectional imaging by CT or MRI (or metabolic imaging) scans may assist with detection of complications, such as abscess, mycotic aneurysm, infarct, or hemorrhage in patients with definite IE. 18FDG-PET/CT for detection of complications of IE. A 65-year-old woman with a mitral bioprosthesis was diagnosed with Staphylococcus aureus IE. TEE revealed a mobile vegetation with leaflet prolapse and severe regurgitation (G and H). On 18FDG-PET/CT imaging, there was 18FDG signal from the mitral bioprosthesis (I and J, white arrow) and evidence of a splenic abscess (I and K, red arrow). SPECT = single-photon emission computed tomography; other abbreviations as in Figure 1.

Routine cross-sectional imaging of the brain, chest, spine, and viscera can be diagnostic and can change management. Imaging cohort studies suggest that patients with IE have a high incidence of subclinical complications, such as embolism, hemorrhage, or abscess. Routine cerebral magnetic resonance imaging (MRI) identifies abnormalities in 80% of patients, and, in 1 prospective study, upgraded 14 (26%) of 53 patients from "possible" to "definite" IE.[73] In another series, CT cerebral angiography identified intracranial mycotic aneurysms in 32% of patients with left-sided endocarditis, of whom 50% subsequently underwent endovascular or neurosurgical intervention.[74] Similarly, MRI imaging of the abdomen identified abnormalities in the spleen, liver, or kidneys in 34% of patients.[75] Evidence of embolism by cross-sectional imaging is a novel minor diagnostic criterion in the ESC 2015 guidelines.

Multimodality assessment by cross-sectional imaging, cardiac CT, and 18FDG-PET or SPECT has the potential to improve diagnosis and detection of complications in patients with suspected IE (Figure 2). We see CT and 18FDG-PET/CT becoming widely used for diagnosis in the "Duke possible" subgroup of patients and for CDI (see later discussion). There are drawbacks, however. Metabolic imaging cannot accurately discriminate between sterile inflammation and infection, and it is therefore of limited use in the early post-operative period. False-positive findings for PET/CT imaging have been reported after cardiac surgery due to post-pericardiotomy syndrome and prosthetic valve thrombosis; they have also been reported at the site of an aortic graft. Access to advanced imaging is often limited, and there is a risk that logistical hurdles may delay definitive surgical intervention. Finally, identifying which patient groups derive the most clinical benefit from advanced imaging (and through precisely which modalities) remains to be established.

Microbiology

Health care–associated organisms have increasingly defined the microbiology of contemporary IE. S aureus is now the most common causative organism and accounts for approximately 30% of cases.[9,10]S aureus endocarditis is characterized by aggressive disease with increased risk of embolism, stroke, persistent bacteremia, and death.[76]S aureus is also the most common cause of PVE, often requiring redo surgery, and is associated with mortality rates approaching 50% in some centers.[77,78] Coagulase-negative staphylococci (CoNS) have a rising incidence of approximately 10% and play a major role in PVE occurring in the first year after the initial procedure.[79,80] Importantly, CoNS have emerged as a cause of NVE, as well as PVE.[81] They are often methicillin resistant and, in the case of Staphylococcus lugdunensis, associated with highly destructive valvular and perivalvular lesions. Oral streptococci comprise approximately 20% of cases, other streptococci approximately 10%, and enterococci a further 10%. HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species), zoonoses, and fungi collectively account for <5% of cases.

Approximately 10% to 20% of patients have negative blood culture findings at presentation, leading to diagnostic uncertainty. Negative results on blood cultures may occur due to previous antibiotic use, infection with fastidious intracellular organisms or fungi, or an alternative diagnosis. The incidence of blood culture–negative IE may drop with increasing use of newer blood culture techniques, which allow direct identification of bacterial species by mass spectroscopy and are significantly faster than standard culture methods.[82]

A rigorous diagnostic approach to patients with blood culture–negative IE allows a causative organism to be identified in two-thirds of patients.[83] The first stage is serological testing for zoonotic agents, specifically Coxiella burnettii (causing Q fever), Bartonella quintana and Bartonella henselae, Brucella species, Myocoplasma species, and Legionella species. If serological findings are positive, blood polymerase chain reaction targeting the causative bacteria should be undertaken. If serological findings are negative, molecular testing of blood or excised valve material is valuable, including broad polymerase chain reaction for bacterial 16S ribosomal ribonucleic acid genes and targeted polymerase chain reaction for Tropheryma whipplei, Bartonella species, and fungi. If microbiological investigation remains negative, consideration should be given to autoimmune disease, and testing for antinuclear antibodies and rheumatoid factor initiated. In a French cohort of 759 patients with blood culture–negative IE, 476 patients ultimately had an identified etiologic agent, most commonly zoonoses (229 Q fever, 86 Bartonella species). Twelve patients were diagnosed with T whipplei, 8 with fungi, and 70 with common bacteria; 19 (2.5%) were found to have noninfectious endocarditis caused by autoimmune disease or marantic endocarditis.[83]

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