Endocarditis and molecular imaging.

Clinically managing acute endocarditis, an infection of the heart valves with a mortality rate of up to 47%, remains highly challenging and frequently unsuccessful (1, 2). The most common pathogen behind acute endocarditis is Staphylococcus aureus, followed by Streptococcus species (2, 3). Unmet clinical needs in treating acute endocarditis include: (i) more reliably diagnosing or excluding endocarditis, (ii) quickly and precisely identifying the pathogen dwelling in vegetations informing selection of antibiotics, and (iii) acquiring more quantitative data to guide decisions about surgical intervention. Currently, clinically diagnosing endocarditis relies on the modified Duke criteria (4), which combine major and minor criteria including echocardiographic imaging, clinical signs such as a new heart murmur or fever, and detection of circulating bacteria in blood cultures. Unfortunately, blood cultures can be misleading; false-negative results occur when the pathogen is present in the vegetation but not in circulation at the time of blood withdrawal, as can occur, for instance, after initiation of antibiotic therapy. The following case report from the Massachusetts General Hospital clinical service highlights this typical problem. Case Report A 71-year-old man with a history of mitral valve prolapse and mitral regurgitation presented with a three-week history of worsening dyspnea on exertion and fatigue. He denied fever, chills, syncope, chest pain, nausea, and vomiting. His temperature was initially 98.0 degrees F with a transient spike to 101 degrees F. His blood pressure was 109/53 mmHg with a pulse of 92 beats per minute. He had a non-painful non-pruritic rash on his lower extremities. Blood cultures were positive for Enterococcus faecalis. Transthoracic echocardiogram (TTE) showed a thickened mitral valve with mitral valve prolapse, severe mitral regurgitation, and a partially flail posterior leaflet, but no definitive vegetation. This result was judged to be unchanged from a prior echocardiography 4 months earlier. He was treated with vancomycin, ceftriaxone, and gentamycin for presumed endocarditis and discharged with a 4-week course of ampicillin and gentamycin. Clinically, the infection seemed to have cleared. Six months later, he underwent elective surgical mitral valve repair. The preoperative transesophageal echocardiogram showed no significant changes from the prior two echo studies, with no definitive evidence of vegetation. During the mitral valve repair, the surgeon observed and then resected a vegetation. Pathologic examination showed infective endocarditis with a fibrin vegetation containing Gram-positive cocci (Fig. 1). This case highlights the limitations of echocardiography: surgery was pursued because echo studies failed to indicate infection. Molecular imaging tools, by contrast, would have detected residual infection and thereby altered clinical management so that the patient could have been treated with another, possibly more specific, course of antibiotics to clear the infection before surgery. Figure 1 Clinical Case of Recurrent Gram-positive Endocarditis SCOPE OF THE PROBLEM AND DIAGNOSTIC GAPS As indicated by the above case report, the clinical diagnosis of endocarditis remains difficult and partially relies on unspecific signs. Guidelines (4) recommend the use of major and minor modified Duke criteria, which include a new or changing heart murmur, fever, detection of circulating bacteria in blood cultures, predisposing conditions, Osler nodes, Janeway’s lesions, splenomegaly, and serial imaging by echo (including transesophageal echocardiograms). These serial echo studies are often done days apart to assess vegetation growth, an important factor in timing surgical intervention (5). However, none of these criteria, except for histological assessment of excised valve material, directly report on bacterial presence in cardiac vegetation. Definite diagnosis is only reached by vegetation pathology, as in the case report presented above, or through several combinations of the aforementioned criteria (two major criteria, or one major and three minor criteria, or five minor criteria)(6). Echocardiograms do not inform on the pathogen and can be false-negative in 15% of cases. Molecular imaging promises to address at least some of these hurdles, as it may provide the opportunity to quantify specific bacteria in endocarditis lesions, akin what currently is only provided by ex vivo histopathology. Disease Origins Endocarditis is a life-threatening inflammation of cardiac endothelium of the heart valve and surrounding tissue that results from an underlying viral, fungal, or bacterial heart infection. Endocarditis is rare in healthy individuals without congenital heart disease but can be fatal due in part to its rapid onset. Broadly, endocarditis is divided into native valve bacterial endocarditis (NBVE) and prosthetic valve bacterial endocarditis (PVBE). Coagulase-positive S. aureus and coagulase-negative S. epidermidis are the major causal pathogens of both types of endocarditis (2, 4). S. aureus endocarditis occurs in approximately 40–50% of neonatal cases and 30–40% of cases in adults 16–60 years, and it has a high mortality rate even with antibiotic therapy (2, 7). In the absence of surgery or a central line causing damage to the heart, vegetations may develop as a result of normal heart valve function (i.e. the mechanical strain of constantly opening and closing). Turbulent flow caused by congenital defects can increase localized pressure that denudes endothelial cells and consequently exposes pro-coagulant surfaces. Such damage is usually repaired quickly, but if bacteria circulate in the blood stream they may attach to the repair site, as illustrated in Fig. 2. Vegetations are predominately composed of platelets, fibrin, and actively replicating bacteria (7). In the late stage of endocarditis, vegetations can lead to valvular stenosis or insufficiency (8), pannus formation in PVBE (9), and, in advanced cases, complete valve destruction via microbe consumption (10). Compromised valve function ultimately leads to heart failure (11). With incidence rising to >15 per 100,000 patients per year, healthcare-associated endocarditis has become a major issue (4). Figure 2 Pathogenesis of S. aureus Endocarditis The majority of life-threatening acute endocarditis cases stem from coagulase-positive S. aureus infections, and streptococcal species are the second most prevalent trigger. More specifically, NVBE is predominantly caused by S. aureus, followed by coagulase-negative staphylococci, enterococci, and Streptococcus bovis infections (12). Although Staphylococcal infections account for the majority of cases, the frequency of Enterococcus and Streptococcus bovis isolation is more than 2-fold greater for patients with diabetes mellitus (13). In the future, next-generation sequencing efforts and whole genome analysis of endocarditis pathogens will show how they adapt during antibiotic therapies. For example, a patient with congenital heart disease was diagnosed with endocarditis, and the pathogen was sequenced from blood collected prior to and during the 12 weeks of therapy, which included rifampin, imipenem, vancomycin, and valve replacement surgery (14, 15). The resulting genomes (JH1-JH9) revealed the timing and frequency of mutations that increase antibiotic resistance and cell survival, thereby providing a glimpse into microbe evolution during disease (14, 15).