Infective endocarditis is a relatively rare but important disease, presenting in a wide variety of forms and manifestations; all are associated with significant morbidity and mortality. The diagnosis and management of infective endocarditis involves many clinical specialties, including internal medicine, cardiology, infectious diseases, microbiology, radiology, cardiovascular surgery, neurology, nephrology, and dentistry.
Definitions and Terminology
Infective endocarditis is a localized microbial infection of cardiac valves or mural endocardium caused by bacteria or fungi. The primary lesion is a vegetation, which is an infected platelet-fibrin thrombus located inside the heart. Native valve endocarditis is an infection of either normal or abnormal natural heart valves, whereas prosthetic valve endocarditis (PVE) involves implanted artificial valves. Nosocomial endocarditis occurs as a complication of medical treatment. On the basis of its clinical course, endocarditis may be classified as either acute or subacute. The acute form, often called acute bacterial endocarditis (ABE), is caused by invasive pathogens and tends to be rapidly progressive, usually leading to hospital admission less than a week after clinical onset and causing death in less than 4 weeks unless successfully treated. The subacute form, often called subacute bacterial endocarditis (SBE), is usually caused by low-grade pathogens or commensal organisms, with symptoms often present for weeks to months before diagnosis. Nonbacterial thrombotic endocarditis (NBTE) and marantic endocarditis refer to sterile vegetations in the heart, which can develop at the same locations as the vegetations of infective endocarditis. Infective endaortitis and infective endarteritis are analogous conditions that are localized on the endothelial surface of the aorta or large arteries, respectively.
Epidemiology
The overall incidence of infective endocarditis ranges from 1.7 to 6.2 cases per 100,000 person-years.1-3 Although the overall incidence has remained relatively stable over the past 5 decades, the relative frequency of the disease in particular subgroups has changed, as have many other aspects of its epidemiology. The median age of patients with endocarditis has increased; 50% of patients are older than 55 years.1,4,5
Among the major predisposing conditions, chronic rheumatic heart disease has become relatively uncommon in developed countries, whereas degenerative valvular diseases, such as calcified aortic stenosis, calcified mitral valve annulus, and mitral valve prolapse have become more important.6 Cases of endocarditis associated with parenteral drug abuse and prosthetic cardiac valves have become more common, as has nosocomial infective endocarditis. Infections involving implanted intravascular devices other than valves are increasing in frequency.
Etiology
Gram-positive cocci, comprising various species of streptococci and enterococci, as well as Staphylococcus aureus, are the leading cause of community-acquired native valve endocardi-tis1-3,6 [see Table 1]. SBE is usually caused by relatively avirulent bacteria, the most common species being streptococci from the normal oral or gastrointestinal flora. These organisms lack sufficient invasiveness to infect normal heart valves or endocardium, but they can infect deformed heart valves and some congenital cardiac lesions. The leading examples are the a-hemolytic streptococci, a heterogeneous collection of species that are loosely grouped together under the term viridans streptococci because they cause incomplete, greenish hemolysis when grown on blood agar.
Many of the streptococci that cause endocarditis can be categorized according to Lancefield serogrouping. About 20% are group D (mainly enterococci and Streptococcus bovis), about 15% are group H (S. sanguis and others), and about 15% belong to other serogroups, including B, C, G, and K. About 5% are anaerobic streptococci, and the remaining 40% to 45% are nongroup-able viridans streptococci.
Enterococcus faecalis, E. faecium, and the nonenterococcal group D streptococcus S. bovis, all of which originate from the GI and genitourinary tracts, are important causes of SBE. The portal of entry for S. bovis is often a malignant or premalignant lesion in the colon.7 Consequently, evaluation for possible colonic lesions is mandated for patients who have developed S. bovis SBE.
Coagulase-negative staphylococci (many of which are species other than S. epidermidis), and fastidious gram-negative HACEK organisms (Haemophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella, Kingella) are other important causes of infective endocarditis. Species that less commonly cause infective endocarditis are Brucella, Legionella, Coxiella bur-netii, Chlamydia psittaci, and Corynebacterium.89 Bartonella, recognized as a cause of infective endocarditis only in the mid-1990s, may account for up to 3% of cases in some regions.10 B. quintana endocarditis occurs more commonly in the homeless, and endocarditis caused by B. henselae may be associated with cats.10-12 Corynebacteria (diphtheroids) usually involve prosthetic heart valves. Endocarditis caused by Coxiella burnetii, a notably indolent infection, occurs in the setting of preexisting valvular dis-ease13 [see 7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella].
ABE is commonly caused by primary pathogens, microorganisms that are more invasive than most of the species causing SBE. These invasive organisms can infect both normal and abnormal heart valves and mural endocardium; can rapidly destroy cardiac valves; can more readily invade perivalvular tissues to form abscesses; and can establish metastatic suppurative foci at distant sites in the body such as the brain or spleen. S. au-reus is the most frequent and most important cause of ABE; others include S. pneumoniae, group A streptococci, Neisseria gonor-rhoeae, Salmonella species, other members of the family Entero-bacteriaceae, and Pseudomonas aeruginosa. Salmonella is the most frequent cause of infective aortitis in the elderly; these patients may have a continuous Salmonella bacteremia in the absence of a cardiac murmur.
Nosocomial endocarditis is a complication of nosocomial bacteremias or fungemias, often associated with intravascular and other indwelling devices, genitourinary tract manipulation, or wound infections.14-18 The primary pathogens are S. aureus, en-terococci, and coagulase-negative staphylococci, most of which are methicillin-resistant S. epidermidis. In parenteral drug abusers, S. aureus (often methicillin resistant) causes 50% or more of cases of infective endocarditis19 [see Table 1].
Fungal endocarditis can be caused by yeasts or molds.20,21 The leading causative agents are yeasts of the genera Candida and Torulopsis; endocarditis from these yeasts arises as a complication of parenteral drug abuse, of prosthetic valves, or of in-travascular devices, such as pacemakers. Endocarditis caused by mycelial or dimorphic fungi is relatively rare but can occur in parenteral drug abusers, patients with prosthetic valves, or im-munocompromised patients. Aspergillus species cause most of these cases; the remainder are caused by Histoplasma, Penicillium, and a wide variety of other fungi.
Pathogenesis
Host factors
Two host factors strongly predispose to development of infective endocarditis: (1) a damaged or otherwise abnormal en-docardial surface and (2) high-velocity, turbulent blood flow across a defective valve or a congenital defect. Both factors favor platelet deposition. When blood is driven from a high-pressure area into a low-pressure sink, the dynamics of pressure gradients and turbulent flow favor deposition of platelets on nearby endothelium, especially if that endothelium is already abnormal as a result of previous disease such as rheumatic fever, congenital abnormalities, degenerative conditions, or infective endocarditis. Subsequently, a form of localized thrombosis can occur, resulting in the formation of a sterile platelet-fibrin aggregate known as nonbacterial thrombotic endocarditis.22 During transient bacteremias, passing microorganisms can adhere to this nidus, which provides them with both nutrition and protection from host defenses, especially leukocytes. The platelet-fibrin layers form an effective physical barrier between the embedded bacteria and leukocytes from the blood. This situation permits luxuriant growth; the organisms often attain vast numbers and form dense colonies within the platelet-fibrin aggregate. The bacteria themselves may promote further thrombosis by elaborating extracellular products that cause platelet aggregation or by eliciting procoagulant tissue factor from the endothelial substrate and local monocytes.23,24 In this way, the newly infected thrombotic lesion grows to form a macroscopic vegetation; these vegetations constitute the prototypical pathologic lesion of infective endocarditis.22
Local host defenses that could inhibit or kill bacteria in the vegetation include leukocytes, antibodies and complement, and platelet-derived bactericidal proteins (thrombocidins).25,26 These antimicrobial host defenses may succeed in curing some early cases of endocardial infection, but apparently they seldom if ever succeed in eradicating the organisms once a vegetation is fully established.
Pathogen factors
The streptococci that most frequently cause SBE—the viri-dans streptococci (including S. mutans, S. mitior, and S. sanguis [group H]), and S. bovis (group D)—readily adhere to platelet-fibrin thrombi, owing to the presence of dextran and other "sticky" molecules (adhesins) on their surfaces.27 Streptococcal species that do not produce dextran may also cause endocarditis, but they do so less frequently. Virulent organisms, such as those associated with ABE, may adhere to either normal or abnormal endocardial surfaces. Fibronectin receptors and clumping factor, which occur on the surface of S. aureus, appear to facilitate the adherence of these organisms to cardiac valves.27-29 Bacterial species that are resistant to platelet-derived microbici-dal proteins are more likely to cause endocarditis than susceptible strains.
Table 1 Causes of Native Valve Endocarditis2,5,6,18,49,109
|
|
Representative Percentage of Cases |
||
|
Microorganism |
Community Acquired |
Nosocomial |
I.V. Drug Abusers |
|
Staphylococcus aureus |
25 |
55 |
55 |
|
Coagulase-negative staphylococci |
3 |
5 |
2 |
|
Streptococci |
35 |
5 |
10 |
|
Enterococci |
10 |
20 |
15 |
|
Gram-negative bacilli |
3 |
5 |
8 |
|
HACEK |
3 |
rare |
rare |
|
Pneumococci |
1 |
rare |
rare |
|
Yeasts and fungi |
1 |
5 |
4 |
|
Polymicrobial and miscellaneous |
5 |
3 |
4 |
|
Culture-negative |
15 |
2 |
2 |
Note: Reported percentages of cases vary widely between many published series.
HACEK—Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella species
Clinical Presentations
Subacute bacterial endocarditis
The constitutional symptoms of SBE usually begin insidiously and often persist for weeks to months. Fevers, sweats, weakness, myalgias, arthralgias, malaise, anorexia, and easy fatigabil-ity are prominent. Fewer than 5% of patients are afebrile, and such patients are often elderly, markedly malnourished, or azotemic. Chills and chilly sensations are common, but frank rigors are unusual.
Because of greater awareness of this disease and more frequent use of blood cultures in the evaluation of febrile illnesses, the diagnosis of SBE is now made earlier than in the past; consequently, many of the classic features of longer-standing SBE (e.g., splenomegaly, clubbing, and Osler nodes) are seldom present. Fever and other nonspecific symptoms in the presence of a predisposing cardiac lesion may be the only clinical manifestations of SBE in some patients. The presenting complaints may arise from organs or sites other than the heart, which may confuse the diagnosis. For example, if the patient has meningitis, cerebral emboli, or glomerulonephritis, the physician’s attention may be focused on the central nervous system or kidneys as the primary site of illness. Although it was once taught that the symptoms of endocarditis in the elderly are milder than in young patients, current data suggest that the clinical features are fairly similar across age groups.30
Figure 1 Findings on physical examination of patients with endocarditis. (a) Erythematous, palpable, nontender lesion at the base of the first finger consistent with a Janeway lesion. (b) Conjunctival petechiae. (c) Pustulonecrotic septic embolic lesions at the base of the nail of the right great toe and at the medial aspect of the left great toe at the level of the distal interphalangeal joint.
Acute bacterial endocarditis
The onset of ABE is usually abrupt, and rigors are com-mon.3132 Fevers reach 39.4° to 40.6° C (102.9° to 105.1° F) and are often remittent. Cutaneous manifestations, particularly petechi-ae and small peripheral infarcts, may be prominent, especially in ABE from S. aureus. Occasionally, the clinical features in a patient with acute S. aureus endocarditis mimic those of acute meningococcemia, with similar skin lesions, including petechi-ae, purpura, and focal gangrene; similar hematologic changes, including disseminated intravascular coagulation; and neurologic findings of nuchal rigidity and CSF pleocytosis. Pustular petechiae or purulent purpura strongly suggest S. aureus endocarditis rather than meningococcemia [see Figure 1]. A Gram stain and culture of material from a skin lesion sometimes can reveal the etiologic agent and thus direct antibiotic therapy.
Emboli are common in ABE. Metastatic infections in the spleen, bones (particularly the vertebrae), joints, kidneys, brain, eye (endophthalmitis), and lungs may arise from either septic embolization or sustained bacteremia. These metastatic infections may cause organ-specific symptoms or persistent fever in spite of antimicrobial therapy and may require drainage or surgical intervention. Osler nodes may occur, but less often than in SBE; Janeway lesions occur in 5% to 10% of patients who have S. aureus endocarditis [see Cutaneous Manifestations, below].
The appearance of a new cardiac murmur, particularly one characteristic of valvular insufficiency, strongly suggests valvular destruction and thus helps confirm a diagnosis of ABE. Valvular damage can lead to severe heart failure, necessitating valve replacement surgery. A few patients with ABE have no detectable cardiac murmur.
Cardiac findings
The cardiac manifestations of infective endocarditis reflect any underlying valvular or congenital lesions, with superimposed findings from endocarditis itself. Murmurs are present in more than 90% of patients. Changes in the intensity of a systolic murmur may be associated with the development of anemia, high fever, or tachycardia and are often of little significance. However, the appearance of a new murmur indicating valvular regurgitation is a key diagnostic event, which also may have implications for surgical intervention. A new aortic diastolic murmur suggests dilatation of the aortic annulus or eversion, rupture, or fenestration of an aortic leaflet. The sudden onset of a loud mitral pansystolic murmur suggests rupture of a chorda tendineae or fenestration of a mitral valve leaflet.
Heart failure resulting from valvular dysfunction may be progressive, becoming severe in some patients. Extension of infection into the annulus may result in cardiac rhythm disturbances, particularly if the infection progresses through the right coronary and noncoronary leaflet portion of the aortic annulus into the membranous septum and the area of the atrioventricu-lar node.33 Occasionally, annular infection extends to the pericardium and causes pericarditis [see Diagnostic Features of Cardiac Complications, below].
Cutaneous manifestations
Petechiae commonly occur in the conjunctivae [see Figure 1], in the oropharynx, and on the skin; they are particularly common on the lower extremities. Petechiae may continue to appear for some time despite appropriate antibiotic treatment. Linear subungual "splinter" hemorrhages located in the base or in the middle of the nail bed are a feature of SBE, whereas splinter hemorrhages in the distal nail bed are more often the result of trauma. Osler nodes—tender, purplish subcutaneous nodules that develop in the pulp of the fingers and disappear within several days—occur in about 5% of patients with endocarditis. Osler nodes may be caused by small emboli or may result from an immunologically mediated small-vessel vasculitis. Small, flat, nonpainful erythematous or hemorrhagic areas on the palms or soles, called Janeway lesions, are common in ABE and also may occur in SBE [see Figure 1].
Musculoskeletal features
Myalgias, arthralgias, arthritis, or low back pain occurs in 40% to 50% of patients with SBE; in about half of these patients, such symptoms represent either initial or prominent manifestations of the disease. Painful, warm, red, tender joints may be noted, but joint effusions are rare. Immunologic mechanisms cause synovial inflammation, articular symptoms, and abnormal laboratory test results. Rheumatoid factor is present in up to 50% of patients with endocarditis of more than 6 weeks’ duration; antinuclear antibody is found in some patients; and circulating immune complexes occur in 75% to 90% of patients. Clubbing of the fingers is now seen in less than 15% of patients.
Ocular findings
Petechial hemorrhages, flame-shaped hemorrhages, Roth spots, and cotton-wool exudates may be seen in the retinas of patients with endocarditis. Roth spots, which are oval white areas surrounded by a zone of bright-red hemorrhage, are noted in 3% to 5% of patients. Such ocular findings are not pathogno-monic of endocarditis; they may be observed in patients with other disorders, such as severe anemia or collagen vascular diseases.
Embolic phenomena
Significant arterial emboli occur in 30% to 50% of patients with endocarditis.34,35 Symptoms and signs include stroke; monocular blindness with occlusion of the central retinal artery; acute abdominal pain, ileus, and melena from mesenteric arterial occlusion; and pain and gangrene in the extremities. Emboli to the CNS are common and especially important, because they adversely affect survival rates and often result in permanent dis-ability.35 Coronary emboli, which are found in as many as 50% of endocarditis patients who undergo autopsy, are often asymptomatic but occasionally result in frank myocardial infarction.
Factors associated with increased risk of embolization include vegetations of 10 mm or more in size as seen on echocardiogra-phy; vegetations on the mitral valve, particularly the anterior leaflet; vegetations that increase in size despite appropriate antibiotic therapy; and infection by S. aureus.3436 The incidence of arterial emboli decreases about 10-fold during the initial 2 weeks of antimicrobial therapy.34 Nevertheless, emboli occasionally occur late, after microbiologic cure has been achieved, and do not necessarily indicate that antimicrobial treatment has failed.
Pulmonary emboli are a common and important complication of right-sided endocarditis, frequently causing pulmonary infarcts or focal pneumonitis. Either may evolve into lung abscess, empyema, or pyopneumothorax, especially when invasive pathogens such as S. aureus are involved.
Splenic abnormalities
Splenomegaly occurs in 15% to 30% of patients with endocarditis. Splenic infarcts occur in up to 40% of patients; they may occur with or without splenomegaly. Splenic infarcts may cause sharp left upper quadrant pain, but they are commonly asymptomatic. Splenic abscesses, which develop in about 5% of patients, may manifest as left shoulder, left upper quadrant, or pleuritic left chest pain; fever that persists during antibiotic therapy; or a relapse of bacteremia. Splenic lesions are best imaged by computed tomography, magnetic resonance techniques, and, to a lesser degree, ultrasonography; however, the differentiation of abscesses from infarcts by imaging is difficult.
Renal manifestations
Microscopic hematuria is observed in about 50% of infective endocarditis patients. Embolic renal infarction may cause flank pain and hematuria, but it rarely causes renal failure. Some degree of acute renal failure occurs in up to one third of patients and is associated with a worse prognosis,37 but it usually resolves
completely if therapy for endocarditis is successful. Diffuse membranoproliferative glomerulonephritis results from immune complex glomerulonephritis, with deposition of IgG, IgM, and complement in a granular or nodular fashion in the glomer-ular basement membrane or on the basement membrane in sub-epithelial or subendothelial locations. Bacterial antigen may be identified in these glomerular deposits. In such patients, serum complement levels usually are reduced. Diffuse membranopro-liferative glomerulonephritis may cause renal failure, which generally resolves after treatment of the infection. Focal embolic glomerulonephritis, originally thought to result from small bacterial emboli, is now recognized as an anatomic variation of immune complex disease. It occasionally causes renal failure.
Mycotic aneurysms
Mycotic aneurysms are arterial aneurysms that develop in association with infections, especially infective endocarditis. My-cotic aneurysms occur in 2% to 8% of infective endocarditis patients and can form in any artery; they are particularly important when they involve cerebral arteries38,39 [see Neurologic Manifestations, below]. They may become symptomatic early, during the active phase of endocarditis, or late, after valvular infection has been eradicated.40 The clinical manifestations, which arise from enlargement or rupture of the aneurysm, include headache, pain, a pulsatile mass, persistent fever despite appropriate antibiotic treatment, focal signs from pressure on adjacent structures, the sudden development of an expanding hema-toma, or signs of major blood loss. Small aneurysms (less than 5 mm in size) may resolve during antibiotic therapy. For larger aneurysms, to prevent possible rupture, therapeutic emboliza-tion, clipping, or excision is usually indicated when such interventions are feasible without undue risk.
