Pathology of Infectious Endocarditis
- Author: Allen Patrick Burke, MD; Chief Editor: Allen Patrick Burke, MD more...
Endocarditis refers to endothelial damage with thrombosis on endocardial surfaces, typically on the heart valves (see the image below). Two major types of endocarditis exist: infectious endocarditis, which has a microbial etiology, and noninfectious endocarditis.
Several terms have been used for these conditions, including (subacute) bacterial endocarditis for infectious endocarditis, and nonbacterial thrombotic endocarditis (NBTE) or marantic endocarditis for noninfectious endocarditis. The term NBTE is still in current use, but this term and subacute bacterial endocarditis are to be discouraged, as not all infections are caused by bacteria.
The population-based incidence of endocarditis is 4-10 per 100,000 per year, with a slightly higher rate in men.[1, 2] The death rate due to endocarditis has been estimated at 1 per 100,000 per year, and it is greater than 10 times that amount in an urban population with a high rate of intravenous drug abuse (IVDA). Endocarditis accounts for about 0.75 admissions per 1000 per year in large community hospitals.
See the following articles for more information:
Etiology and Pathophysiology
Endocarditis begins as endothelial damage and sterile surface microthrombus, which, in the absence of bacteremia, regresses or grows into macrothrombi (noninfectious endocarditis).
Malformed stenotic or regurgitant valves
Malformed stenotic valves, or especially regurgitant valves, are predisposed to endocarditis. In the presence of bacteremia or fungemia, even transient or those with low microbe counts, microthrombi become infected, by adhesion and colonization of the thrombotic surfaces. Growth of organisms results in an inflammatory response, with neutrophil infiltration, enlargement of the thrombus, recruitment of matrix metalloproteinases (MMPs), and eventual destruction of collagen and cusp perforation. In approximately 25% of patients, however, neither structural valve abnormalities nor predisposing conditions are evident.
Valve abnormalities, disease, prosthesis, and previous surgery
Congenital valve abnormalities, acquired valve disease, prostheses, and previous cardiac surgery for structural congenital heart disease increase the risk for endocarditis and are indications for antibiotic prophylaxis for dental and other invasive procedures. In nosocomial endocarditis, bacteremic conditions are present in nearly 40% of cases and include intravenous drug abuse, hemodialysis, catheterizations, and intravascular devices.
The organisms responsible for most cases of infectious endocarditis are gram-positive cocci: streptococci and, increasingly, staphylococci. The most common microbial infection is staphylococcus. Hospital-acquired infection is often associated with hemodialysis, prosthetic valvular infection, malignancies, and vascular interventions.
Some cases of culture-negative endocarditis are caused by fastidious gram-negative organisms of the Haemophilus parainfluenzae, Actinobacillus, Actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae (HACEK) group, which constitutes approximately 1-3% of cases of community-acquired endocarditis on native and prosthetic valves, and may have a relatively good prognosis.
Organisms causing community-acquired endocarditis include the following:
Staphylococcus aureus (30-50%; minority, methicillin-resistant Staphylococcus aureus [MRSA])
Alpha-hemolytic (viridans) streptococci (10-35%)
Culture negative (5-30%)
Fungi (< 5%)
Staphylococcus epidermidis (coagulase negative; < 5%)
Others (eg, Escherichia coli, Klebsiella, Corynebacterium; < 5%)
Organisms responsible for nosocomial endocarditis include the following:
S aureus (60-80%; majority, MRSA)
Alpha-hemolytic streptococci (< 5%)
Culture negative (5%)
S epidermidis (coagulase negative; < 5%)
Others (eg, E coli, Klebsiella, Corynebacterium; 5-10%)
The rate of culture-negative endocarditis varies from 7% to 33% and is increased in community-acquired infections because of antibiotic treatment before diagnosis. No association exists between culture negativity and underlying etiology or risk factors. If a full work-up is performed at a tertiary reference center, including serology and culture for esoteric organisms and polymerase chain reaction (PCR), an etiology is found in over 75% of cases of endocarditis with an initial negative culture. The most common organisms are C burnetii and Bartonella species.
Endocarditis generally refers to inflammation on the valve leaflets, although the endocardial lining of the atrium and ventricles may also be involved, especially after surgery. The process tends to begin on the lines of closure, where the pressure is greatest (atrial surfaces of the atrioventricular valves and the ventricular surface of the semilunar valves).
The valves most commonly infected are left-sided valves, with approximately equal frequency between the mitral and aortic valves (see the following images). Vegetations on the mitral valve can extend onto the noncoronary and left cusps of the aortic valve, as they are contiguous, and double aortic and mitral valve replacements are not rare. Left-sided valve endocarditis is more frequent, even in drug addicts, than right-sided endocarditis, although infections of the tricuspid and pulmonary valves are highly suspicious of intravenous drug abuse.
Tricuspid valve endocarditis may occur in community-acquired infection, usually in intravenous drug addicts, or hospital-acquired infections from implanted devices. Isolated pulmonary valve endocarditis is rare (except in patients with congenital heart disease) and may cause confusing clinical symptoms.
The clinical symptoms of infectious endocarditis may be general (related to the infectious agent) or specific (related to the site or heart valve affected) and related to valvular insufficiency, with concomitant infectious symptoms. The classic signs of Osler nodes and Janeway lesions are increasingly uncommon, but microembolic phenomena such as splinter hemorrhages, Roth spots, and glomerulonephritis are still frequently observed in patients in the 21st century. Previously, infectious endocarditis has been diagnosed using clinical criteria (Duke criteria), dividing cases into possible and probable endocarditis. Current imaging modalities, especially transesophageal echocardiography and computed tomography (CT) scanner, have largely supplanted other tests.
Treatment of infectious endocarditis includes antibiotics, and, possibly, surgery if the valve is irreversibly insufficient. Surgical options include replacement, and repair if possible. In general, between 14% and 37% of cases require surgery.
Prognosis and Predictive Factors
The overall mortality of infectious endocarditis is approximately 20-25%, and it is increased with advanced patient age, left-sided disease, methicillin-resistant S aureus (MRSA) infection, and chronic renal failure. For staphylococcal endocarditis, mortality is associated with age 60 years or older, female sex, community-acquired infection, absence of heart murmur, presence of congestive heart failure, and central nervous system involvement. The mortality rate of MRSA endocarditis in hemodialysis patients is as high as 90%. The long-term prognosis of patients with negative blood culture infective endocarditis has been found to be similar to that of patients with positive blood culture infective endocarditis across all age ranges.
Gross Pathologic Findings
In infectious endocarditis, the valve may appear hemorrhagic and roughened, in early or treated lesions, with vegetations that may be inconspicuous or large. Especially bulky vegetations are typical of fungal endocarditis. Perforation of the valve leaflet is nearly pathognomonic for a later stage endocarditis, because only infectious processes result in significant valve tissue destruction (see the image below). In autopsy specimens, discrete areas of endocardial fibrosis, or jet lesions, may be seen on the atrial surfaces in cases of atrioventricular valve endocarditis, or the ventricular outflow in aortic or pulmonary endocarditis.
Upon autopsy, or with complete valve replacement, many valves demonstrate underling pathology such as bicuspid aortic valve, mitral valve prolapse, or postinflammatory valve disease, predisposing the patient to endocarditis (see the images below).
A study by Shrestha et al concluded that valve sequencing, not valve culture, should be considered the primary test for identifying bacteria in excised cardiac valves.
Microscopic Pathologic Findings
Two features are always present in infectious endocarditis: inflammation and surface thrombus. Depending on the duration of the infection and treatment, the inflammation may be primarily neutrophilic or mostly chronic. Macrophage giant cells are common, especially toward the luminal surface. Organizing and organized thrombi with fibrosis are common in lesions that have been present for weeks or more. In acute lesions, clusters of organisms are frequently found, often gram-positive cocci, with the acute exudate and surface thrombus. See the following images.
The most common valve lesion in patients with lupus is related to the antiphospholipid syndrome, and histologically they are indistinguishable from thrombi (nonbacterial thrombotic endocarditis or marantic endocarditis). True inflammatory autoimmune valvulitis is rare and has gone by the eponymic term Libman-Sacks endocarditis, in the case of lupus.
Immunohistochemistry (IHC) has been used for the detection of fastidious bacteria in cases of culture-negative endocarditis, specifically for Coxiella and Legionella infection. Immunohistochemical studies of these organisms are generally restricted to reference laboratories with special expertise in identifying infectious agents.
Polymerase chain reactions (PCRs) have been used for the detection of DNA types that are specific for fastidious bacteria in culture-negative bacteria. Specific organisms that have been tested in this way include rickettsia (Coxiella, Bartonella, and Tropheryma whipplei [Whipple disease]).
The following articles provide more detailed information regarding infectious endocarditis:
Thiene G, Basso C. Pathology and pathogenesis of infective endocarditis in native heart valves. Cardiovasc Pathol. Sep-Oct 2006;15(5):256-63. [Medline].
Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. Aug 1 2006;114(5):e84-231. [Medline].
Butany J, Dev V, Leong SW, Soor GS, Thangaroopan M, Borger MA. Infective endocarditis of the tricuspid valve. J Card Surg. Nov-Dec 2006;21(6):603-4. [Medline].
Jegatheeswaran A, Butany J. Pathology of infectious and inflammatory diseases in prosthetic heart valves. Cardiovasc Pathol. Sep-Oct 2006;15(5):252-5. [Medline].
Castonguay MC, Burner KD, Edwards WD, et al. Surgical pathology of native valve endocarditis in 310 specimens from 28 patients. Cardiovasc Pathol 2013;22:19-27.
Fonager K, Lindberg J, Thulstrup AM, Pedersen L, Schønheyder HC, Sørensen HT. Incidence and short-term prognosis of infective endocarditis in Denmark, 1980-1997. Scand J Infect Dis. 2003. 35(1):27-30. [Medline].
Walpot J, Blok W, van Zwienen J, Klazen C, Amsel B. Incidence and complication rate of infective endocarditis in the Dutch region of Walcheren: a 3-year retrospective study. Acta Cardiol. 2006 Apr. 61(2):175-81. [Medline].
Burke AP, Kalra P, Li L, Smialek J, Virmani R. Infectious endocarditis and sudden unexpected death: incidence and morphology of lesions in intravenous addicts and non-drug abusers. J Heart Valve Dis. 1997 Mar. 6(2):198-203. [Medline].
Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980-1990. A review of 210 episodes. Medicine (Baltimore). 1993 Mar. 72(2):90-102. [Medline].
Chen SC, Dwyer DE, Sorrell TC. A comparison of hospital and community-acquired infective endocarditis. Am J Cardiol. 1992 Dec 1. 70(18):1449-52. [Medline].
Krcmery V, Hricak V, Babelova O. Culture negative endocarditis: analysis of 201 cases. Scand J Infect Dis. 2007. 39(4):384. [Medline].
Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference center: etiologic diagnosis of 348 cases. Medicine (Baltimore). 2005 May. 84(3):162-73. [Medline].
Watanakunakorn C. Staphylococcus aureus endocarditis at a community teaching hospital, 1980 to 1991. An analysis of 106 cases. Arch Intern Med. 1994 Oct 24. 154(20):2330-5. [Medline].
Kuo CB, Lin JC, Peng MY, Wang NC, Chang FY. Endocarditis: impact of methicillin-resistant Staphylococcus aureus in hemodialysis patients and community-acquired infection. J Microbiol Immunol Infect. 2007 Aug. 40(4):317-24. [Medline].
Shrestha NK, Ledtke CS, Wang H, Fraser TG, Rehm SJ, Hussain ST, et al. Heart valve culture and sequencing to identify the infective endocarditis pathogen in surgically treated patients. Ann Thorac Surg. 2015 Jan. 99 (1):33-7. [Medline].
Eiken PW, Edwards WD, Tazelaar HD, McBane RD, Zehr KJ. Surgical pathology of nonbacterial thrombotic endocarditis in 30 patients, 1985-2000. Mayo Clin Proc. 2001 Dec. 76(12):1204-12. [Medline].