I. INTRODUCTION. Infective endocarditis (IE) is the most severe and potentially devastating complication of heart valve disease, be it native valve (NVE), prosthetic valve (PVE), or infection on another cardiac device. Without treatment, IE is uniformly fatal, and the old concepts of acute, subacute, and chronic endocarditis only referred to the time it was anticipated to take before the patient died. Even in the current therapeutic era, with appropriate antibiotic therapy and surgical intervention, multicenter studies report in-hospital mortality of 15% to 20% and 1-year mortality approaching 40%. Patients with valve disease, prosthetic valves, cardiac devices, a history of IE, immuno suppression, dialysis, drug abuse, and other medical situations are at increased risk of IE. As a paradoxical effect of advances in medical and surgical therapy, the incidence of IE has increased during the past 30 years. This is due to an increase in the number of patients with risk factors for IE, including an increasing elderly population with degenerative valve disease and a rise in staphylococcal infections. It is extremely uncommon for normal valves to become infected, but it does happen.
The clinical scenarios presented by patients with IE are often very complex. At the same time, IE requires prompt diagnosis for early institution of antibiotic treatment and decision-making related to complications, including risk of embolism and need for and timing of high-risk surgery. IE patients require a multispecialty team approach: an infectious disease specialist, cardiologist, and cardiac surgeon constitute the core of this team, but input from other specialties, most often neurology, is often required. Execution of the operation with radical debridement and reconstruction of the heart and heart valves requires experience and special expertise. Despite advances in surgical techniques, operations for IE remain associated with the highest mortality of any valve disease, even at the most experienced centers.
II. PATHOGENESIS AND PATHOLOGY, MICROBIOLOGY, AND LEFT- VERSUS RIGHT-SIDED IE
A. Causative organism, position (aortic, mitral, or right-sided), and type of infected valve (NVE or PVE) are of great importance to pathology and prognosis. The factors responsible for the ability of the organisms to infect, survive, and destroy are called virulence factors, and include those that allow the organism to attach to the infection site, avoid the host’s immune response, and produce destructive enzymes, toxins, protective substances, and other factors.
B. A valve becomes infected when circulating organisms adhere to damaged endothelium of a native or prosthetic valve. The organisms multiply, develop vegetations, and produce toxins and enzymes that disintegrate valve tissue and allow extravascular invasion.
A great variety of organisms can cause IE, and they differ with regard to virulence factors, which determine their aggressiveness. The microbiology of IE depends on whether the valve is native or prosthetic and whether the infection is community or hospital acquired. Staphylococci, streptococci, and enterococci are the most important causative organisms, responsible for approximately 85% of all IEs. Staphylococci and streptococci are the most common aggressive and destructive bacteria causing IE.
Although Staphylococcus aureus
is more common with NVE, Staphylococcus epidermidis
is a more common cause of PVE. Fungi form large vegetations but are usually less invasive, although Aspergillus
IE is associated with development of mycotic aneurysms. We have recently described the progression and pathologic stages of NVE and in a PVE atlas (see Pettersson, Hussain, Shrestha, 2014
D. Despite introduction of antibiotics, IE has remained notoriously difficult to treat, and even extended courses of high-dose antibiotics often fail to cure the infection. Recent research has provided a plausible explanation for this by introducing the biofilm hypothesis. Biofilm development and quorum sensing are social bacterial behaviors. Bacterial populations produce and live embedded in a self-produced, extracellular, polysaccharide slim matrix, and quorum sensing is a chemical cell-to-cell communication mechanism that synchronizes gene expression and activates the maturation and assembly of the biofilm in a coordinated manner. The biofilm provides protection against the host’s immune system and is a difficult barrier for antimicrobials to penetrate. Ability to form biofilm is a characteristic of the bacteria commonly causing IE, including staphylococci, streptococci, and enterococci. Surgery effectively disrupts the biofilm and exposes residual bacteria to circulating antimicrobials, antibodies, and active immune cells.
E. Tissue disintegration and invasion caused by toxins and enzymes result in serious complications, including heart failure from valve regurgitation or fistulae. Extravascular invasion causes abscesses around the aortic root or in the atrioventricular (AV) groove, potentially leading to heart block. Embolism of pieces of vegetations can cause stroke, mycotic aneurysms, and other embolic phenomena. Destroyed tissue does not regrow; valves made leaky by bacterial destruction will not heal and become competent even if the infection is cured by antibiotics.
F. Outcomes after treatment of IE are often related to whether it is a native or a prosthetic valve infection. Prosthetic valve infections are generally more invasive and more difficult to treat and cure with antibiotics only. Formation of biofilm protecting the organisms offers an explanation to why surgery is more often needed for PVE.
G. When comparing aortic and mitral valve IE, we have observed that aortic valve IE is more invasive (true for both NVE and PVE) and that it is responsible for a higher proportion of prosthetic valve infections. Despite this, outcomes are worse after surgical treatment of mitral IE than after aortic IE. We identified three reasons why mitral IE is more difficult to deal with: Mitral valve patients are sicker, surgical anatomy is less favorable, and we do not have an allograft valve replacement alternative for the mitral valve. In another recent, as yet unpublished study, we looked at the difference in invasiveness between left-sided and right-sided IE and confirmed that right-sided IE is never invasive, although it is caused by the same aggressive organisms as S. aureus. Our hypothesis is that invasion is driven by high pressure, although oxygenated blood on the left side could also be a factor, because most bacteria that cause IE are aerobic.
H. Systemic emboli, with emboli to the brain being the most frequent and important, are very common in patients with left-sided IE. Although rare, systemic septic emboli can cause mycotic aneurysms in any artery, in any location, including the aorta. Right-sided IE frequently sends septic emboli to the lungs, with development of pulmonary abscesses.
III. THE VALUE OF SURGERY IN THE TREATMENT OF IE
Studies that question the value of surgery use methodology that takes into account “survival bias” and “referral bias”—the self-selection of patients surviving long enough to be considered for surgery—by looking at entire populations with IE to study whether or not addition of surgery improves outcomes. Surgeons at large referral centers are limited to studying patients who are still alive and referred with “surgical” complications; thus, referral and survival bias will always be an issue in outcome studies from such centers. However, with the current improved outcomes, there is general agreement, supported by guidelines, that surgery should play a major role in managing IE. Kang
and coworkers recently published a randomized study specifically studying timing of surgery for IE and were able to provide evidence supporting early surgery (within 48 hours) rather than waiting for heart failure to develop. We have been proponents of early surgery for a long time, taking the patient to the operating room as soon as a surgical indication has been identified.
B. All patients diagnosed with IE are primarily treated with antibiotics, initially broad spectrum and then adjusted to sensitivity pattern once this is known. Antibiotics to which the organisms are sensitive suppress the infection, may prevent or halt further destruction, and, if treatment is initiated early enough, may cure the patient. Antibiotics will not, however, restore the integrity of damaged tissue and valves.
The hypothesis that IE is a biofilm-associated infection explains why it is difficult to treat this infection and its recurrence after seemingly successful treatment, and why surgery is often required for cure in addition to antibiotics. Surgery mechanically disrupts the biofilm and removes the vegetations, infected necrotic tissue, and foreign material and drains the infected areas, thereby improving the access of antimicrobials. In addition, valve repair or replacement restores valve function and cardiac integrity. Still, final cure is the result of antibiotics. Most experienced groups, including ours, are convinced that surgery is beneficial and are becoming increasingly aggressive about advocating earlier surgery rather than waiting for complications. This evolution is based on improved outcomes after surgery and the growing conviction that there is a small price to be paid for operating on patients with active infection, and duration of preoperative antibiotic treatment has no or minimal impact on outcomes.
IV. DIAGNOSIS OF IE
A. IE is suspected from the patient’s history and symptoms. Clinical presentation varies according to the causative organism, preexisting cardiac disease, comorbidities, and complications. IE may present as an acute, rapidly progressive infection or as a subacute or chronic disease with recurrent episodes of fever and malaise. Fever, often associated with systemic symptoms of chills, night sweats, poor appetite, and weight loss, is a typical symptom. Clinical findings include a new murmur or a change in an existing murmur, and embolic phenomena like petechiae, Roth spots, Osler nodes, and Janeway lesions. Neurologic events with stroke are the most serious, occurring in 20% to 40% of all patients, whereas mycotic aneurysms are much less common. A high index of suspicion and low threshold to exclude IE are essential to diagnosis and early treatment. Echocardiography and blood cultures are the cornerstones of diagnosing IE.
B. Echocardiography remains the most important imaging modality in securing the diagnosis. Transesophageal echocardiography (TEE) is more sensitive than transthoracic echocardiography (TTE) and is the present gold standard diagnostic modality for documenting IE. Echocardiographic findings of IE include vegetations, periprosthetic leakage in patients with PVE, intracardiac fistulae, and abscess cavities. The echocardiographic examination is excellent at evaluating valve function, but less reliable for assessing severity and invasiveness of the infection. A negative echocardiogram does not exclude the diagnosis of IE. Echocardiography has a better yield in patients with NVE than PVE, and shadowing is a particular problem in patients with mechanical valve prosthesis. TTE must be performed first, but both TTE and TEE should be performed in the majority of cases of suspected or definite IE. The added value of cardiac computed tomography (CT) and magnetic resonance imaging (MRI) remains controversial. In most patients with IE, MRI will demonstrate abnormal consistency of tissue in the annulus.
Whenever possible, a bacteriologic diagnosis should be secured before starting antibiotics. When IE is suspected, ideally three or more blood cultures should be collected before antibiotics are initiated, and at least two should be obtained immediately from different peripheral sites. Additional blood cultures should be obtained a few hours later. Unless the patient is septic, it is appropriate to hold off on starting antibiotics until an adequate
number of blood cultures have been collected. Blood cultures from separate sites are usually positive in patients with bacterial endocarditis; two positive cultures out of three is considered diagnostic. Although diagnostic methods have improved, cultures in patients with fastidious organisms or fungi may take more than 3 weeks to become positive. Cases of IE in which blood cultures are negative (10%) may reflect either that the patient had been treated with antibiotics before the blood culture was drawn or that the infection is caused by fastidious organisms. For cases caused by fastidious organisms, either serologic testing or valve polymerase chain reaction assay can identify the pathogen 60% of the time. Typical microorganisms causing IE include Streptococcus viridans, Staphylococcus aureus, S. epidermidis, Streptococcus bovis,
a HACEK group organism (Haemophilus
spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella
spp., and Kingella kingae
), or community-acquired enterococci.
The modified Duke criteria (Table 16.1
), based on clinical, echocardiographic, and microbiologic findings categorized as major and minor criteria, provide high sensitivity and specificity (˜80% overall) for the diagnosis of IE. However, clinical judgment remains essential, especially in clinical scenarios with negative blood cultures, PVE, and so forth, where sensitivity of the Duke criteria is reduced.
V. INDICATIONS AND TIMING OF SURGERY
A. Patient management is discussed by a multispecialty team dedicated to managing patients with IE. This team should include a cardiologist, an infectious disease specialist, and a cardiac surgeon. A neurologist and sometimes a neurosurgeon become involved when neurologic complications are present, and a nephrologist may be needed to manage renal failure. A psychiatrist and a social worker help manage drug addicts. Other specialists are consulted as required for a particular patient. As per the 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines for IE, decisions about timing of surgical interventions should be made by a multispecialty Heart Valve Team of cardiology, cardiothoracic surgery, and infectious disease specialists and is a class I recommendation.
Recommendations for diagnosis and treatment of IE based on 2014 AHA/ACC guidelines are presented in Figure 16.1
. Standard indications for surgery in patients with IE are presented in Table 16.2
. In patients with NVE, congestive heart failure is the most frequent and severe complication of IE and is a class I indication for surgery. Presence of invasive disease with extravascular extension and IE caused by “difficult to treat” organisms associated with continued fever and sepsis after institution of appropriate antibiotic therapy are reasons for early surgical intervention. Surgical treatment should be considered in patients with signs of congestive heart failure, acute valve dysfunction, invasion with paravalvular abscess or cardiac fistulae, recurrent systemic embolization, or persistent sepsis despite adequate antibiotic therapy for more than 4 to 5 days.
C. Surgery to prevent embolism in patients with large mobile vegetations is a more controversial indication. Location, size, and mobility of the vegetation; previous embolism; type of organism; and duration of antibiotic therapy influence the indication for surgery. Mobile large vegetations >10 mm on the anterior mitral valve leaflet have been proven to be associated with higher embolic risk. We have tended to be more aggressive in these cases as we have become more confident that the penalty for operating on patients with active IE is indeed low and the valve is usually possible to preserve.
D. For patients with uncomplicated, nonstaphylococcal, and late PVE, treatment with antibiotics alone may be worth trying, but often the infection will recur within a few months. In patients with less aggressive bacteria, for example, enterococci, vegetations may be miniscule and the infection noninvasive, thus making the diagnosis very difficult. Patients with invasive staphylococcal PVE and early PVE require early surgery.
Approximately half of patients with IE develop severe complications that sooner or later require an operation. Early surgery as advocated by Kang and coworkers and by our group means operating for any of these conditions before heart failure has
developed. In the study of Kang et al., the most frequent preventable complication in the conventional treatment group was embolic stroke. For this reason, once there is a surgical indication, surgery should not be delayed.
TABLE 16.1 Modified Duke Criteria for the Diagnosis of Infective Endocarditis (IE)
Blood culture positive for IE
Typical microorganisms consistent with IE from two separate blood cultures:
Viridans streptococci, S. bovis, HACEK group, S. aureus; or
community-acquired enterococci, in the absence of a primary focus
Microorganisms consistent with IE from persistently positive blood cultures, defined as follows:
At least two positive cultures of blood samples drawn >12 hr apart; or
All of three or a majority of ≥4 separate cultures of blood (with first and last sample drawn at least 1 hr apart)
Single positive blood culture for Coxiella burnetii or antiphase I immunoglobulin antibody titer >1: 800
Evidence of endocardial involvement
Echocardiogram positive for IE (transesophageal echocardiography recommended in patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE [paravalvular abscess]; transthoracic echocardiography as first test in other patients), defined as follows:
Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or
New partial dehiscence of prosthetic valve
New valvular regurgitation (worsening or changing of preexisting murmur not sufficient)
Predisposition: predisposing heart condition or injection drug use
Fever: temperature >38°C
Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions
Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor
Microbiologic evidence: positive blood culture but does not meet a major criterion as noted above or serologic evidence of active infection with organism consistent with IE
Diagnosis of IE is definite in the presence of
Two major criteria, or
One major and three minor criteria, or
Five minor criteria
Diagnosis of IE is possible in the presence of
One major and one minor criteria, or
Three minor criteria
Adapted from Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633-638, with permission of Oxford University Press; HACEK group (Haemophilus spp. Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella kingae).
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