Jean P. Hartin Del Castillo, Isabella Rosa-Cunha Infective endocarditis (IE) refers to a microbial infection within the endothelium of the heart. Vegetations form and adhere to the endothelial structures. The heart valves are most often involved, but the disease may also occur within a septal defect, on the chordae tendineae, or on the mural endocardium. The majority of IE cases are the result of bacterial infections. However, increasing numbers of cases of IE caused by fungal, chlamydial, and rickettsial organisms have been reported; hence the change in name from bacterial endocarditis to infective endocarditis.1–5 Despite diagnostic and therapeutic advancements, IE remains a life-threatening disease associated with serious complications and carries a high mortality. Historically, IE has been classified as acute or subacute according to its clinical course. Acute IE is a fulminant process; death can occur within days to less than 6 weeks. The usual culprit organisms are Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Neisseria gonorrhoeae. Subacute IE (death occurring within 6 weeks to 3 months) and chronic IE (death occurring later than 3 months) are usually classified together. These two forms of IE have a more subtle, indolent course; the usual causative organisms are the viridans streptococci. Although classifications based on acuity are helpful, a more descriptive system has been introduced and is of greater therapeutic and prognostic value. IE may be classified according to the evolution of the disease, the infectious pathogen, and the presence of a preexisting disease or risk factor (e.g., acute native valve endocarditis [NVE] involving viridans streptococci).3,6,7 Currently more than half of patients diagnosed with IE are older than 50 years; the ratio of male to female patients is greater than 2:1.4 Although the overall incidence of IE is relatively low, certain populations are at higher risk, including but not limited to users of injectable drugs; individuals with structural cardiac abnormalities, implantable devices, or cardiac and vascular prostheses; immunosuppressed patients; and individuals with a history of IE.2,3 In the United States alone, approximately 10,000 to 15,000 new IE cases annually as well as an alarming 20% to 30% mortality rate have been reported.2 S. aureus is the most common cause of IE in the industrialized world, mainly because of development of risk associated with health care contact.2,3,4,7 Successful management of IE requires a multidisciplinary collaborative effort in this extremely challenging population of patients.1–4,7 NVE is the most common type of IE and affects the mitral valve (28% to 45%), the aortic valve (5% to 36%), and both mitral and aortic valves (35%); the tricuspid valve is rarely affected (0% to 6%).3,7,8 Predisposition to NVE seems to be greatest when structural heart disease has created a defect, resulting in turbulent blood flow.3,4 Any structural heart disease (e.g., rheumatic heart disease, mitral valve prolapse, congenital heart disease) or degenerative cardiac lesion (e.g., calcification of the mitral annulus, calcified nodular lesions secondary to atherosclerotic disease, post–myocardial infarction thrombus) may predispose a patient to IE. In many countries rheumatic heart disease is still a common cause of IE; it has been implicated in 37% to 76% of infections.3 IE has been associated with mitral valve prolapse, especially in the setting of mitral valve regurgitation. Mitral valve prolapse without mitral insufficiency is a more common abnormality and is associated with a small risk of endocarditis. Previous endocarditis is a risk factor for IE owing to the valvular damage that results from the infection.3,8 Congenital heart disease anomalies including bicuspid aortic valve, patent ductus arteriosus, ventricular septal defect, coarctation of the aorta, bicuspid aortic valve, tetralogy of Fallot, and pulmonic stenosis account for 10% to 20% of the cases.2 Advances in the management of structural abnormalities and surgical correction of congenital abnormalities have significantly reduced the number of individuals at risk for IE.2,3,6,8 IE can occur on valves that are morphologically normal; in recent years, an increasing number of patients have no detectable predisposing cardiac lesion. Other predisposing factors for NVE are advanced age, diabetes, injection drug use, long-term hemodialysis, and immunosuppression, including human immunodeficiency virus (HIV) infection.4,9 Streptococcal and staphylococcal species account for 80% of NVE in non–injection drug users.2,3 Higher mortality is seen in patients with S. aureus infection, diabetes, advanced age, and IE complications (stroke, congestive heart failure [CHF], paravalvular abscess). S. aureus is the culprit organism in most cases of acute IE; it causes systemic toxicity, often with metastatic infection, and carries a 40% mortality.3,5 Viridans streptococci are normal inhabitants of the oropharynx and account for approximately 30% to 40% of all streptococcal IE.2,3 Streptococcus bovis, a group D Streptococcus species, is the causative organism in a small percentage of cases and is strongly associated with malignant or premalignant gastrointestinal lesions; therefore evaluation for colon cancer should be conducted in patients with S. bovis IE.2 Group B streptococci are normal flora of the gastrointestinal tract, oropharynx, vagina, and urethra in 5% to 12% of the population. Group B streptococci account for less than 5% of cases, yet these organisms are capable of affecting normal valves, leading to rapid destruction of the valve and embolization of vegetative matter. Mortality rates can approach 50%.2,3 Enterococci are indigenous to the gastrointestinal tract and urethra; the number of IE cases caused by enterococci appears to be increasing. IE caused by enterococci is usually seen in both older men and younger women who have a recent history of genitourinary surgery, trauma, or malignant disease. Albeit rarely, it may also occur in women who have undergone an obstetric procedure.2,3 Other potential pathogens in NVE include fastidious gram-negative organisms grouped by the acronym of HACEK (Haemophilus aphrophilus [subsequently called Aggregatibacter aphrophilus and Aggregatibacter paraphrophilus]; Actinobacillus actinomycetemcomitans [subsequently called Aggregatibacter actinomycetemcomitans]; Cardiobacterium hominis; Eikenella corrodens; and Kingella kingae). These organisms are components of the flora of the oropharynx and upper respiratory tract and account for approximately 3% to 10% of cases of IE in patients who do not use injection drugs.2 Although the clinical course is typically subacute, these organisms are capable of producing large friable vegetations with high risk of embolization, causing CHF and often necessitating valve replacement. Although it was previously difficult to identify the HACEK organisms, they are now reliably isolated with automated blood culture systems.2,3,5 NVE caused by other gram-negative organisms including Pseudomonas species and Escherichia coli is rare and usually associated with central venous catheters and implantable endovascular devices. Recent health care contact is common in these patients.3 Fungal IE represents less than 5% of NVE cases. Candida and Aspergillus species account for the majority of fungal endocarditis, usually in patients with predisposing conditions including but not limited to central venous catheters, dialysis catheters, prosthetic valves, immunosuppression, and implanted cardiac devices. Large vegetations often develop, extension into surrounding tissue and apparatus is seen, and surgical intervention frequently is required. The prognosis remains poor, despite aggressive combined medical and surgical interventions.2,5 Culture-negative endocarditis occurs in 5% to 15% of cases of IE. It is usually associated with previous exposure to antibiotics or infection with extremely fastidious organisms or intracellular bacteria that cannot be routinely cultured in blood with the standard blood culture techniques, including Bartonella species and Coxiella burnetii. Close work with the microbiology and pathology laboratories can help to identify organisms that may require longer incubation periods, enhanced culture mediums, special serology testing, and tissue biopsy 2,3,7 Prosthetic valve endocarditis (PVE) comprises 10% to 20% of all IE cases and occurs with similar frequency in both the aortic and mitral valves. The first 12 months after valve replacement surgery represent the highest risk of infection; bioprosthetic and mechanical prostheses are infected with similar frequency.2,3,9–11 Risk factors associated include prior NVE, long cardiopulmonary bypass time during valve replacement, and male sex. PVE is categorized as early when symptoms occur within 60 to 365 days after surgery, or late when symptoms occur more than 1 year after surgery; the time frame usually relates to the varying virulence of the organisms. Early PVE is usually nosocomial, and the result of perioperative or immediate postoperative infection; it occurs either intraoperatively through direct contamination of the surgical field or postoperatively through contamination of central lines, pacemaker wires, or other indwelling sources. Despite prophylactic antibiotic therapy, the majority of early infections are the result of S. aureus, coagulase-negative staphylococci, or fungi.3,7,10 The organisms involved in PVE are similar to those seen in NVE. Infections associated with early PVE usually result in rapid valvular dysfunction and destruction of the integrity of the suture line, thus heralding an acute and rapidly deteriorating course with a high morbidity and mortality rate. Streptococcus species, enterococci, gram-negative bacilli, and diphtheroids are often involved within the first year after surgery.3,7,10 Because late PVE is often caused by less virulent organisms, it usually has a subacute course;, however, if the offending organism is virulent, late PVE may also manifest as an acute, fulminant infection. Common presentations in PVE include but are not limited to CHF, conduction system abnormalities, valve dehiscence, and regurgitant murmurs.7 Late fungal endocarditis accounts for 10% to 15% of cases and carries a higher mortality.2,3,9 Staphylococci, streptococci, and enterococci are the organisms mainly responsible for community-acquired late PVE.3,7 PVE usually requires a combination of medical and surgical approaches.2,5 Those who develop endocarditis associated with injection drug use tend to be 20 to 40 years of age (80%) and are most often male (4:1).3,5 The actual risk of infection among injection drug users is variable, depending on the drugs injected, the method of preparation, and the frequency of use. In this population, infection involving the tricuspid valve or in combination with another valve is most common (50% to 60%). Up to 75% of these patients may develop septic pulmonary emboli.2,3 Right-sided endocarditis is otherwise rare; therefore injection drug use should be suspected. Involvement of the mitral valve alone is seen in 10.8% of cases, and in the aortic valve, 18.5% of cases. Involvement of both the aortic and mitral valves is seen in 12.5% of patients. The majority of individuals (66% to 75%) who develop IE have structurally normal valves before the infection; a minority have an underlying cardiac lesion from congenital heart disease or previous endocardial infection. Use of injection drugs predisposes the patients to recurrent and polymicrobial IE.2,3 Skin flora is the most common source of pathogenic microorganisms in users of injection drugs; contaminated drugs and drug paraphernalia are also bacterial sources. S. aureus is the most common offending organism; it is isolated in 50% to 60% of total cases and tends to be less virulent in IE originating from the right side. Streptococcus species, Pseudomonas aeruginosa, polymicrobial infections, and diphtheroids have also been implicated as causative pathogens.2,3,5 Right-sided endocarditis is associated with pneumonia and septic pulmonary emboli as a result of direct embolization in approximately 75% to 85% of patients. These patients appear ill, with high fevers and shaking chills. Patients with a clinical syndrome consistent with tricuspid valve endocarditis should also be evaluated for a potential extracardiac source of the endovascular infection, such as septic thrombophlebitis. The overall mortality rate for right-sided endocarditis is approximately 2% to 6%, whereas left-sided involvement is associated with a much higher mortality.2,5 Health care–associated endocarditis refers to IE in patients with history of out-of-hospital health care system contact (e.g., wound care, care in a dialysis center or specialty nursing home, or chemotherapy within the last 30 days; or hospitalization for 2 or more days within the last 90 days). Community-acquired IE is defined as diagnosis within 48 hours of admission, without extensive health care contact. Non-nosocomial IE is defined as the occurrence of symptoms within 48 hours of hospital admission, with extensive health care contact. Nosocomial IE is defined as IE that is diagnosed more than 48 hours after hospital admission.3,7 Data suggest that most cases of nosocomial and non-nosocomial IE are caused by S. aureus, and at higher rates than previously reported; Enterococcus species were second in frequency.3,9 Most patients with health care–associated IE had indwelling central catheters, were on hemodialysis, had undergone recent surgical procedures, or were immunosuppressed. A study of hospitalized patients on hemodialysis through a central venous catheter indicated a 28% IE rate (mainly isolated was S. aureus); the overall death rate was 55.6%, and death occurred in all with methicillin-resistant S. aureus.12 Permanent pacemakers and implantable cardioverter-defibrillators are examples of cardiovascular implantable electronic devices (CIEDs). Advances in cardiovascular device technology have had a positive impact on patient outcomes with respect to quality and quantity of life. According to the American Heart Association, implantation rates for permanent pacemakers and implantable cardioverter-defibrillators increased dramatically over the study period from 1993 to 2008.13 With the population living longer and greater numbers of devices being implanted, rates of infection have markedly increased to 0.13% to 0.19%; infection may occur in the device pocket or leads as well as in valvular or nonvalvular endocardium.2,13 Elevated risk of infection also appears correlated to the following: advanced age; comorbid conditions (diabetes, CHF, malignancy, renal failure); device revision; absence of preprocedure antibiotic prophylaxis; hematoma formation; inexperienced operators, and low-volume implantation centers.13,14 Early infections, within 6 months of implantation, are generally caused by skin flora organisms, mainly Staphylococcus species. Those organisms demonstrate the ability to form biofilm. Biofilm is an accumulation of bacteria on bacteria, adherent to the surface of the device and encased in extracellular slime; this dense formation of bacteria is more resistant to antibiotics as well as to host defenses.13,15 The development of endocarditis depends on the invasion of the bloodstream by a pathogen capable of attaching to an endothelial surface. The normal endothelium is not conducive to bacterial deposition. A high-velocity jet stream, a narrow valvular orifice, and a flow from a high- to a low-pressure chamber are hemodynamic features that predispose the patient to endocarditis. The forceful flow denudes the endothelium and allows platelet and fibrin deposition. The layering of platelets and fibrin creates nonbacterial sterile vegetation (nonbacterial thrombotic endocarditis [NBTE]), which in turn provides an ideal medium for bacterial adherence and growth.3,16 Virulent microorganisms, especially the staphylococcal species, are capable of attaching to even normal endothelium.3,4 Microorganisms typically attach just distal to the narrowed orifice of a turbulent jet, such as on the atrial surface of the mitral leaflets in mitral regurgitation or on the ventricular surface of the aortic cusps in the setting of aortic insufficiency. After colonization of the endothelial surface, bacteria begin the replication process. Further platelet and fibrin deposition over the bacteria provides insulation from phagocytic cellular defenses, which allows the microorganisms to thrive and to form vegetations. Proliferation of the microorganism leads to local valvular destruction, tissue invasion, and possible embolization of the vegetative material.2–4 Morphologic characteristics of the vegetations depend on the offending organism and the duration of the infection. Lesions range from small, flat, or granular deposits to large, pedunculated, and friable formations. During the course of effective antimicrobial therapy, leukocytes and fibroblasts penetrate vegetations. This healing process results in fibrosis, occasionally with calcification, and eventual re-endothelialization of the valvular surface.3 Embolization of vegetative matter is not uncommon and most often involves the renal, splenic, coronary, or cerebral circulation. Myocardial infarction can be the result of embolization of the vegetative material to the coronary arteries. Pulmonary embolism is a complication associated with right-sided endocarditis in injection drug users, or in individuals with fungal infections. Embolization of septic material can lead to abscess formation. Mycotic aneurysms occur as a direct result of septic invasion into the arterial wall or septic embolization, which weakens the vessel wall and predisposes it to rupture.3 Persistent bacteremia triggers an immune complex response of both the humoral and cell-mediated immune systems. As seen in many chronic infections, a generalized hypergammaglobulinemia develops. Immune complexes containing immunoglobulins G, M, and A along with complement are deposited along the glomerular basement membrane of the kidney, precipitating glomerulonephritis. Peripheral manifestations of arthritic discomforts and cutaneous vasculitis may also be attributed to deposition of immune complexes in the joints and mucocutaneous vessels.3,7 The onset of symptoms usually occurs within days to weeks of the introduction of the microorganisms, but the symptoms may initially be nonspecific. Early symptoms of infection include generalized fatigue, malaise, night sweats, chills, weight loss, weakness, nausea and vomiting, and anorexia. A highly pathogenic organism such as S. aureus may manifest with an abrupt onset that prompts the patient to seek early medical attention. The virulence of the invading microorganism, underlying health of the patient, duration of infection, valvular structures involved, and presence or absence of CHF dictate the pace and severity of the disease course.1–3 Fever is present in the majority of patients but may be absent in older adults, immunocompromised hosts, patients with CHF or renal failure, or patients previously treated with antibiotics.2–4 The degree of fever depends on the causative microorganism; high-grade fevers are primarily associated with virulent organisms and acute infections. Most patients defervesce with 3 to 7 days of appropriate antimicrobial therapy; however, fever may be protracted in some patients, usually resolving within 2 weeks of treatment. Persistent fever may suggest drug failure, secondary infection, an ineffective antimicrobial regimen, or intracardiac or extracardiac abscess formation.2,3,7 Evidence of cerebral emboli may be seen in approximately 20% to 30% of patients with IE, and is the most common clinical neurologic finding. In recent studies, there is indication of a higher rate of cerebral emboli, varying from 65-82%; the formerly lower rate is due to silent presentations of IE. Even with appropriate therapy, stroke is seen in 4.82 cases per 1000 patient-days in the first week but improves by nearly two thirds in the second week.3 Staphylococcal IE may manifest with neurologic phenomena as the first sign. The middle cerebral artery is the most commonly involved territory. Mycotic aneurysms are potentially life-threatening complications that occur in a small percentage of patients. They typically occur early in the course of the disease but can occur months or even years after a bacteriologic cure has been achieved. A severe unrelenting headache, transient neurologic changes, or signs of cranial nerve involvement suggest the possibility of an intracranial mycotic aneurysm. Brain abscesses, seizures, purulent meningitis, arteritis, cerebral emboli, intracerebral bleeding, subarachnoid hemorrhage, and encephalopathy have also been reported.2,3,5,7 A complete funduscopic examination in those diagnosed with or suspected to have IE is recommended. Roth spots are exudative, edematous hemorrhagic lesions of the retina. They may cause changes in visual acuity. Endogenous endophthalmitis can be one of the consequences of IE; usual symptoms are decreased vision and/or eye pain. It can cause severe vision impairment and vision loss.3 The signs and symptoms of IE vary according to the causative organism and the degree of systemic involvement. Valvular infection can result in the disruption of valvular integrity, including perforation of a valve leaflet, rupture of chordae tendineae or papillary muscles, and leaflet prolapse. Penetration of bacteria into the adjacent myocardium can result in myocardial or perivalvular abscesses, which may contribute to development of conduction system disturbances, heart block, and pericarditis.7 Further penetration of infection may produce fistulas between cardiac chambers. Large vegetations associated with fungal or Haemophilus infections can cause obstruction of the valvular orifice. Even after a bacterial cure has been achieved, fibrosis of the valve leaflets can result in hemodynamically significant valvular stenosis or regurgitation.3 Heart murmurs are detectable in the majority of patients but may be absent early in the course of the illness, in patients with right-sided endocarditis, or in older adults. A new murmur of regurgitation or change in an existing murmur suggests an acute, virulent process and often heralds the development of CHF. The diagnosis of IE must be entertained in any patient with a new heart murmur or a change in an existing heart murmur and fever of unknown origin.2–4,7 CHF, regardless of acuity, predicts a grave prognosis; poor surgical outcome is also demonstrated. Nevertheless, substantially reduced mortality rates are seen in the individual who undergoes valve surgery, if necessary. CHF may be secondary to valvular destruction, rupture of one of the chordae, obstruction of the valve by bulky vegetations, coronary embolization resulting in myocardial infarction, myocarditis, myocardial abscess formation, or prosthetic dehiscence.2,3,5 Pulmonary embolism is most often associated with tricuspid valve endocarditis in injection drug users. It may also occur in patients with indwelling central venous catheters or in patients with left-sided endocarditis who have left-to-right shunting from a septal defect.2,5 Patients may have clinical pulmonary signs and symptoms; abnormal chest x-ray findings, pleural effusion, infiltrates or pneumonia, pleuritic chest pain, and cough with or without blood-streaked sputum. Pneumothorax may also be a complication of septic pulmonary emboli.3 Splenomegaly has declined significantly, with rates reported at 11%, possibly because of increasing acute IE and/or shorter time to diagnosis. Splenic septic emboli, although common, are usually asymptomatic. Prolonged fever or localized symptoms should prompt CT scan to rule out splenic abscess. Petechiae may be noted on the conjunctivae, palate, buccal mucosa, and extremities; they are present in 20% to 40% of patients and usually only for the first few days. Splinter hemorrhages are linear, subungual hemorrhages appearing in the proximal nail bed; common in subacute IE, they are also found in patients of advanced age or in the setting of occupational trauma.2,3 Janeway lesions and Osler nodes are cutaneous lesions associated with endocarditis. Janeway lesions are nontender, hemorrhagic macules (1 to 4 mm) on the palms and soles and are the result of septic embolization. Osler nodes are painful nodules on the finger and toe pads that last hours to days. They have also been noted on the forearms, ears, and dorsa of the feet and are associated with immune complex deposition. The resulting inflammatory response leads to swelling, redness, and pain that characterize these lesions. Osler nodes are rare in acute IE but are present in 10% to 25% of subacute cases; they are not specific to IE. Clubbing may be seen in 10% to 20% of patients with subacute IE or more prolonged cases, and may improve with therapy.2,3
Infective Endocarditis
Definition and Epidemiology
Native Valve Endocarditis
Native Valve Endocarditis Risk Factors.
Native Valve Endocarditis Infectious Organisms.
Prosthetic Valve Endocarditis
Endocarditis in Injection Drug Users
Health Care–Associated Endocarditis
Cardiac Implantable Electronic Device Endocarditis
Pathophysiology
Clinical Presentation and Physical Examination
Fever
Neurologic Findings
Ophthalmologic Findings
Cardiac Findings
Pulmonary Findings
Splenic and Dermatologic Findings
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Infective Endocarditis
Chapter 123
