Cardiovascular Infections

Larry M. Baddour, William K. Freeman, Rakesh M. Suri, Walter R. Wilson

Historically, the focus of cardiovascular infections has been on infective endocarditis (IE) as the primary syndrome. In this chapter, infections that involve cardiovascular devices, including permanent pacemakers, implantable cardioverter-defibrillators, coronary stents, and ventricular assist devices, also are addressed, because infection is a frequent complication with some devices, often necessitating their removal. Moreover, the indications for devices continue to expand, involving an increasing number of patients, particularly among aging populations in many developed countries. These devices may be lifesaving and improve quality of life, but device removal generally is required for infection cure, and removal procedures are associated with notable morbidity and mortality. Certain aspects of antimicrobial therapy also are unique, inasmuch as IE often is caused by multi-drug–resistant organisms acquired in the health care setting. Consequently, fewer drugs are available for treating these infections, with an increased likelihood of drug-related toxicities. In addition, longer durations of therapy may be needed, which can enhance the rate of drug-induced adverse events.

Infective Endocarditis

Before the pandemic of human immunodeficiency virus infection, IE was the syndrome for which the expertise of infectious diseases physicians was almost universally requested. IE has the proclivity to cause complications both at the cardiac valve site and at extracardiac locations that can predispose affected patients to serious morbidity and mortality. It is for these reasons that management of IE requires a team approach, which generally includes specialists in infectious diseases, cardiovascular medicine, and cardiovascular surgery with particular expertise in IE. Thus every patient with IE should be managed in the inpatient setting of a medical center with experienced medical and surgical specialists to provide care, which often includes emergent diagnostic and surgical interventions.

Epidemiology

The global burden of disease due to IE is largely unknown. Much of the world’s population lives in developing countries, where many people do not have routine access to advanced medical care. In addition, in most of these countries, no infrastructure exists on either a local or countrywide level for disease reporting (see Chapter 2). Thus the clinical characterization of IE is a biased one that is shaped by the collective experiences at large teaching facilities in countries where patient access is available and disease reporting is done. However, even in many developed countries, including the United States, IE is not included among the diagnoses requiring mandatory reporting to public health agencies that would define a statewide or national disease incidence or burden.

IE is a heterogeneous syndrome that is heavily influenced by the epidemiology of the infection. For example, in developing countries where rheumatic fever is still endemic, younger adults with long-standing rheumatic heart disease commonly present with a subacute clinical course spanning several weeks that involves left-sided native valve infection due to viridans group streptococci. By contrast, in large, teaching, tertiary care centers in developed countries, patients with previous health care exposure frequently present with an acute illness that can be measured in days and is due to Staphylococcus aureus, with numerous anatomic sites of metastatic foci of infection and worse outcomes.

The incidence of IE is influenced by multiple host factors that modify the risk of infection. Such factors include the underlying anatomic (usually valvular) cardiac conditions that result in turbulent blood flow and endothelial cell disruption (see the Pathogenesis section). In addition, aging of the population in developed countries has resulted in a greater number of patients with myxomatous degeneration of the mitral valve with subsequent prolapse and insufficiency (see Chapter 63), while at the same time a dramatic fall in the incidence of rheumatic fever has reduced the overall risk of IE in younger persons. Advances in medicine also alter the incidence of IE. For example, reduced use of tunneled catheters with an increasing use of arteriovenous fistulas for chronic hemodialysis will reduce the risk of bloodstream infection. Improvement in oral health in developed countries also may affect the incidence of IE, but this remains to be determined.

Population-based studies¹^,² have been used to estimate both the incidence of IE and its clinical characterization, but complete case ascertainment is difficult to secure. For example, in the United States, patients may receive medical care in locations that are not in their place of residence. Thus large medical centers that have unique expertise in endocarditis management may be unable to obtain complete case ascertainment in a population owing to changing referral patterns or second-party coverage. Data generated from a population-based investigation will have limited applicability (generalizability) if the cohort under study is not representative of other populations in demographic or clinical features,.

Incidence studies of IE are limited in number and in geographic coverage of populations.¹^,² The incidence reported among surveys from Western Europe and Olmsted County, Minnesota, has been stable for many years, at fewer than 10 cases per 100,000 person-years, with the exception of one analysis³ from northwestern Italy that demonstrated a small but statistically significant increase in incidence. Historically, a sex predilection has been noted, with males more often affected by IE. This is due in part to a major contribution of injection drug use, which more frequently is reported among men, but even in cohorts with IE and a low frequency of reported injection drug use, males still predominate. This male predominance may be fading, as reported in a recent analysis² in which the female incidence had increased, with a high level of health care exposure cited as a predisposing condition for the development of IE. Thus access to health care can influence the epidemiology of IE.

Health care exposure, including both nosocomial and nonnosocomial exposure, has been recognized only recently²^,⁴ as a major contributor to the development of IE. Not only do indwelling central venous catheters and hemodialysis predispose to bloodstream infection, but infection with antimicrobial resistant pathogens is more likely to occur as a consequence of health care–related exposure. The virulence of some of these pathogens, in particular, methicillin-resistant S. aureus (MRSA), is notable and is associated with increased mortality in patients with IE.

Injection drug users are a unique group at increased risk for IE. Thus the modified Duke criteria⁵ include injection drug use as a “minor” criterion to satisfy a case definition of IE. These patients, who tend to be young, male, and otherwise healthy, account for a large proportion of IE cases in inner city medical centers in developed countries.⁶ Their contact with the health care system often is limited to short stays in an emergency department. Some patients, however, harbor chronic bloodborne viral infections, including those due to hepatitis viruses and human immunodeficiency virus, often unrecognized until the affected person presents with manifestations of IE and undergoes subsequent screening for viral infections not directly related to heart valve infection. The predominant pathogen involving this group of patients with IE is S. aureus; less common is a panoply of other organisms, including aerobic gram-negative bacilli and anaerobic and aerobic oral flora, with polymicrobial infections also seen in a minority of patients. Patients tend to delay seeking medical care and present with systemic complications of infection. Because the right side of the heart, especially the tricuspid valve associated with heroin use,⁶ commonly is involved, patients often present with pulmonary complications, including septic pulmonary emboli, empyema, and lung abscesses. In a minority of patients, bilateral IE develops, with complications involving both the pulmonary and systemic circulations. Although outcomes of injection drug–using patients with right-sided IE generally are good, these patients are well recognized to be at risk for recurrent bouts of IE, particularly if they continue injecting illicit drugs and if prosthetic valve placement was required to treat the previous valve infection.

Microbiology

Any of a vast array of bacteria and fungi can cause IE,⁷ as is evident in novel case reports and literature reviews of IE due to unusual organisms. Although changes in the prevalence of pathogens causing IE have emerged in recent years owing to critical changes in the epidemiology of IE in developed countries,²^,⁸ the overall distribution of infecting organisms has remained the same, with gram-positive cocci being predominant. These include streptococcal, staphylococcal, and enterococcal species. Important virulence factors unique to each genus group appear to be operative in infection pathogenesis (see later under Pathogenesis). It is therefore not surprising that the modified Duke criteria⁵ listed only these three groups of pathogens as “typical microorganisms” in the designation of the major criterion of “blood culture positive” for IE.

Streptococcal Species.

Among streptococci, the viridans group streptococci are the predominant organisms that cause IE. A “subacute” presentation is typical, with symptoms of infection present for weeks to a few months, with low-grade fever, night sweats, and fatigue being common. These organisms normally are found in the mouth of humans and tend to cause indolent infections. Sustained bacteremia due to this group of bacteria should prompt a consideration of the diagnosis of IE, as few other infection syndromes cause sustained bloodstream infection. The viridians group includes several evolving species of streptococci and currently includes sanguis, oralis (mitis), salivarius, mutans, intermedius, anginosus, and constellatus. The latter three species have been referred to the S. anginosus or S. milleri group and are unique in that they have a proclivity to produce abscess formation and metastatic infection foci, both within the heart and in extracardiac locations in patients with IE.

The viridans group streptococci also include species of Gemella, Abiotrophia, and Granulicatella. For Gemella, one species designated as morbillorum used to be listed in the Streptococcus genus. These organisms can cause IE and exhibit metabolic characteristics akin to those of the “nutritionally variant streptococci,” which have now been reassigned to the Abiotrophia and Granulicatella genera. The recommended medical therapy for infections due to these unique organisms is discussed subsequently (see the Antimicrobial Therapy section).

Viridans group streptococci constitute the predominant cause of native valve infection acquired in the community setting, in both developing and developed nations. A common substrate for infection due to these organisms has been rheumatic valvular disease, but as mentioned previously, the incidence of acute rheumatic fever has fallen dramatically in developed countries.

Similar to other bacteria, viridans group streptococci have developed resistance to some antibiotics. Fortunately, resistance to penicillin is seen in a minority of IE isolates. Resistance is not based on beta-lactamase production, and the definitions used⁷ to characterize strains as being penicillin-resistant are not the same as the breakpoints recommended by the Clinical and Laboratory Standards Institute (CLSI). This distinction can be confusing for some clinicians, because selection of antibiotic therapy is based on in vitro susceptibility results (see Antimicrobial Therapy section).

Unlike viridans group streptococci, beta-hemolytic streptococci typically cause an acute presentation of IE. Injection drug users and elderly persons are two at-risk groups. Complications are frequent and often involve valve destruction and distant sites, often musculoskeletal, of infection. The prevalence of beta-hemolytic streptococci among cases of IE is less than 10%. Beta-hemolytic streptococci have remained uniquely susceptible to penicillin, with extremely rare exception. Nevertheless, it is prudent to obtain susceptibility testing on all isolates. Surgery is often required for management of severe valvular and perivalvular involvement.

Streptococcus gallolyticus (formerly known as S. bovis) deserves particular attention. The organism usually is found in the gastrointestinal tract, and when it is recovered from blood culture, whether related to IE or not, an examination for an underlying gastrointestinal lesion, including colon cancer, should be performed. Although it currently is the cause of less than 10% of cases of IE, the expectation is that it will become more prominent in aging populations and in populations with increasing restrictions on cancer prevention screening.

Historically, IE due to Streptococcus pneumoniae has received considerable attention. Although it continues to be a common cause of community-acquired bloodstream infection that often is related to pneumonia, it is a rare cause of IE today. When it does cause IE, the clinical presentation usually is that of an acute syndrome associated with valve destruction. It can be associated with meningitis as well as other intracranial complications. Invasive isolates of pneumococci tend to be penicillin-susceptible, but susceptibility testing is required to confirm this impression. As with IE due to beta-hemolytic streptococci, surgery often is required to address valve-related complications.

Staphylococcal Species.

The staphylococci are the second group of gram-positive cocci that are well recognized as causes of IE. S. aureus is a common cause of both native and prosthetic valve endocarditis.⁷^,⁸ The presentation in cases caused by S. aureus is acute in onset and associated with considerable systemic toxicity. In cases of left-heart infection, morbidity and mortality rates are high, despite appropriate therapy including surgical intervention. Right-heart infection, predominantly of the tricuspid valve in injection drug users, has a much higher cure rate than that for left heart infection, and mortality rates are low, unless bilateral infection is present. Unfortunately, the rate of IE due to S. aureus is increasing, owing in part to an increased exposure to health care. In addition, resistance to oxacillin and other antibiotics also has increased, which has made treatment more difficult.

Although coagulase-negative staphylococci are recognized as frequent pathogens of prosthetic valve infection, they also can cause native valve infection in a minority of IE cases. Although these infections usually are subacute in presentation, the morbidity and mortality associated with IE due to coagulase-negative staphylococci are considerable. Of the more than 30 species of coagulase-negative staphylococci, two deserve special attention: Staphylococcus epidermidis is the most commonly identified species to cause bacteremia and IE. Staphylococcus lugdunensis is another species that causes both native and prosthetic valve endocarditis and tends to be more virulent than the other species of coagulase-negative staphylococci. Because this group of organisms is the most common cause of contaminated blood cultures, a delay in diagnosis can occur, due to misinterpretation of blood culture results. Multiple sets of blood culture specimens should therefore be collected to better distinguish contamination from bloodstream infection. Except for S. lugdunensis, many strains of which remain penicillin-susceptible, coagulase-negative staphylococci are more drug-resistant than S. aureus; accordingly, fewer treatment options are available.

Enterococcal Species.

Age is strongly associated with the development of IE due to enterococcal species, with the prevalence of these organisms in IE cases doubling among elderly persons as compared with young adults. A majority of infections are due to Enterococcus faecalis and are associated with genitourinary tract abnormalities. In the past, enterococcal IE was community-acquired, and enterococci were well recognized as part of the normal gut flora in humans. More recently, enterococcal species associated with health care exposure and central venous catheter use have contributed to infection predisposition. With this group of organisms, a subacute IE presentation is typical, and antibiotic therapy requires penicillin or ampicillin combined with an aminoglycoside, usually gentamicin. Multidrug-resistant enterococcal species, in particular, Enterococcus faecium, can cause IE that is difficult to cure; this includes infection due to vancomycin-resistant strains collectively termed vancomycin-resistant enterococci (VRE).

HACEK Organisms.

The HACEK organisms are fastidious gram-negative bacilli comprising Haemophilus species (other than Haemophilus influenzae), actinomycetemcomitans (formerly Actinobacillus actinomycetemcomitans), Aggregatibacter aphrophilus (formerly Haemophilus aphrophilus), Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, and Kingella denitrificans). They colonize in the oropharynx and upper respiratory tract, causing subacute IE presentation that is community-acquired. Most of the organisms in blood cultures may require several days of incubation. Owing to the indolent clinical course, diagnosis often is delayed, with the formation of large vegetations observed at echocardiography. As a result, embolism to the brain or other systemic sites occurs frequently.

Aerobic Gram-Negative Bacilli.

In view of their universal causation of bloodstream infection, it is noteworthy that IE due to aerobic gram-negative bacilli is rare. This observation attests to the unique virulence factors that characterize gram-positive cocci in IE pathogenesis that are not found in gram-negative bacilli. This group includes Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas species, and others. In cases of IE caused by these organisms, presentations generally have been acute and sometimes associated with systemic toxicity, including sepsis and its complications. IE can be either community- or health care–associated. Outcomes of IE due to aerobic gram-negative bacilli are characterized by increased morbidity and mortality rates.

Fungi.

Fungi are extremely rare causes of IE. Identification of these organisms often is difficult, because some of them do not grow in routine blood culture media. Even when selected culture media are used, fungal isolation may not be achieved. Thus fungi can cause either blood culture–positive or culture-negative IE.

The bulk of these infections are due to Candida species, although a broad array of fungi may cause IE. These infections usually are health care–associated and involve prosthetic valves, often arising as a result of a central venous catheter infection. An indwelling right-heart catheter, such as a flotation catheter, can denude a valve and/or nonvalvular endothelial surface, thereby predisposing the patient to fungal (or bacterial) right-sided IE. In addition, injection drug use is a well-recognized risk factor for fungal IE.

Clinical presentations range in severity from acute to subacute. Complications are frequent, and surgical intervention is recommended as a routine intervention, particularly with infections due to molds such as Aspergillus species. Because relapsing IE is a concern and can be delayed in onset, many clinicians advocate the use of lifelong oral antifungal-suppressive therapy, usually with an azole, after initial parenteral therapy is completed.

Culture-Negative Endocarditis.

For a majority of cases that are designated as blood culture–-negative endocarditis, the pathogen is not recovered from blood cultures owing to the patient’s recent exposure to an antimicrobial that had suppressive or killing activity against the pathogen. In addition, with some uncommon causes of culture-negative endocarditis, the pathogen either will not grow in routine blood culture media or grows slowly in the media and is not detected in the time interval used for blood cultures. In the former scenario, nothing can be done. In the latter, blood cultures can be held for an extended period, at least 14 days, to determine if an isolate is recovered. Other techniques, such as special culture methods or serologic studies, also are used to isolate or identify infection. Organisms that should be included in this category include fungi, Coxiella burnetii, Bartonella species, Brucella species, Tropheryma whipplei, and Legionella species.

Pathogenesis

Investigations that examine pathogenic mechanisms will likely lead to the development of future novel therapies, many of them unrelated to the traditional activities of antimicrobial agents that will be used in the management and prevention of IE.

Two overarching aspects of endocarditis pathogenesis have been identified.⁷ Already noted is a primary predilection for development of IE due to an underlying valvular or nonvalvular cardiac structural abnormality that results in blood flow turbulence, endothelial disruption, and platelet and fibrin deposition. This lesion, termed nonbacterial thrombotic endocarditis (NBTE), serves as a nidus for subsequent adhesion by bacteria or fungi in the bloodstream. This pathway is thought to account for a majority of cases of IE, most often related to left-sided valvular stenosis or regurgitation. This picture of pathogenesis is mirrored, in many ways, by the animal model of endocarditis that has been used for decades to examine the pathogenesis, treatment, and prevention of IE. The microbiologic and histopathologic findings in infected animals are reflective of those seen in humans. A second notion is that infection may involve normal valves. Some reservations regarding this pathway of infection seem appropriate, because it is impossible to know if a valve is completely normal, including its endothelial surface, before onset of valve infection. In addition, animals do not develop experimental endocarditis after an intravascular challenge with a relatively large inoculum of virulent organisms, in particular S. aureus, in the absence of a previous disruption of the cardiac endothelial surface. Nevertheless, in vitro endothelial cell cultures studies have demonstrated uptake of organisms by endothelial cells.

The predominance of gram-positive cocci as causes of IE deserves additional comment. Advances in molecular biologic techniques have resulted in the ability to define virulence factors that are unique to these organisms.⁹ Infectivity studies that have compared “wild type” parent strains to molecularly “engineered” strains using an experimental IE model have been of critical importance in defining virulence factors among strains of staphylococci, streptococci, and enterococci. Some of these factors serve as “adhesins” and are largely responsible for initial bacterial attachment to an NBTE nidus or to endothelial cells. They also are responsible for the attachment to medical devices, including prosthetic valves and cardiovascular implantable electronic device (CIED) leads. In this regard, biofilm formation occurs with some of these organisms and is important in both native tissue and prosthetic valve infections in the context of factors that are responsible for the propagation of IE after initial bacterial attachment.

The findings from these investigations are expected to affect future treatment and prevention of IE. Novel vaccines containing bacterial proteins that function as adhesins and are good immunogens are being examined, for example, and already have proved to be efficacious in the prevention of experimental IE. In this case, the protein (FimA)¹⁰ is expressed by several species of viridans group streptococci in the pathogenesis of IE. In addition, it is conceivable that work focusing on treatment and prevention of dental caries by viridans group streptococci could have some role in the management and prevention of IE.

Clinical Presentation

Predisposing Cardiac Conditions

Predisposing conditions to IE have evolved over the decades since early clinical series were reported. More recently, the International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS)⁸ has detailed the clinical presentation in 2781 patients with definite IE. Native valve IE was predominant (72%), followed by prosthetic valve endocarditis (21%) and pacemaker or ICD IE (7%). Consistent with numerous earlier series, this international cohort study found that IE manifests with definite vegetations most commonly in the mitral valve position (41%), followed by the aortic valve position (38%), whereas the tricuspid (12%) and pulmonary (1%) valves were much less frequently involved.⁸

Preexisting valvular regurgitant lesions are far more prone to infection than stenotic lesions. It has been suggested that the incidence of IE is directly related to the impact of pressure on the closed valve, with shear stress disruption of the valvular endothelium in the vicinity of the egressing regurgitant jet. In the presence of the Venturi effect, circulating organisms are deposited within the high-velocity, lowered-pressure eddy zones of the regurgitant orifice of the receiving chamber, leading to the typical localization of vegetations on the upstream aspect of the infected valve.

Mitral regurgitation associated with degenerative mitral valve prolapse, particularly with advanced myxomatous leaflet thickening, is the most common predisposing condition for IE and is far more common than rheumatic mitral valve disease.⁸ Functional mitral regurgitation, associated with left ventricular (LV) remodeling causing mal-coaptation of intrinsically normal mitral leaflets in a low-pressure, low-cardiac-output state, also is quite uncommonly complicated by IE. The second most common native valve lesion predisposing to IE is aortic regurgitation. The risk of IE in patients with bicuspid aortic valve is low, with an incidence of approximately 2% during follow-up periods ranging from 9 to 20 years.¹¹^,¹² Bicuspid aortic valve, however, is relatively common (16% to 43%) in case series of confirmed aortic valve IE,¹³^,¹⁴ is associated with a high incidence of periannular complications of IE (50% to 64%), and is a strong independent predictor of perivalvular extension of infection.¹³ In patients older than 65 years of age, nonrheumatic aortic stenosis is seen as the aortic valve lesion in IE at a rate almost three times that of younger patients (28% and 10%, respectively).¹⁵

Congenital heart disease, other than bicuspid aortic valve disease, is a predisposing condition to IE in approximately 5% to 12% of cases¹^,⁸^,¹⁶ Unrepaired ventricular septal defects are the most frequent congenital heart disease lesions associated with IE, followed by ventricular outflow tract obstructive lesions, such as with tetralogy of Fallot.¹⁷ Any highly turbulent shunt lesion can predispose affected patients to IE, as can the presence of prosthetic material employed for palliative shunts, conduits, or shunt closures, particularly if a residual shunt is present after surgical intervention. Low-velocity/low-turbulence shunt lesions, such as secundum atrial septal defect, are far less prone to endocardial disruption and are associated with a very low incidence of IE.¹⁷

A number of additional conditions contribute to the above anatomic cardiac lesions in the predisposition to risk of IE. These include a history of previous IE, the presence of chronic intravenous access, intravenous drug abuse, and indwelling endocavitary devices. Predisposing general medical conditions include diabetes mellitus, underlying malignancy, renal failure requiring hemodialysis, and chronic immunosuppressive therapy.⁸^,¹⁶ A history of an invasive or dental procedure can be identified in approximately 25% of patients within 60 days of clinical presentation with IE.⁸ A history of cardiac disease may be present in approximately 50% to 65% of patients.¹⁸ Superimposed and of mounting concern is the increasing frequency of health care–associated IE. In a recent report from the ICE-PCS investigators,¹⁹ 19% of the cases in a study cohort of 1622 patients with IE were considered to be nosocomial (defined as related to hospitalization for more than 2 days before presentation with IE). An additional 16% of cases were related to non-nosocomial health care (e.g., outpatient hemodialysis, intravenous chemotherapy, wound care, or residence in a long-term care facility) received within 30 days of onset of symptoms of IE.

Symptoms.

The presentation of IE encompasses a broad spectrum of symptoms and is influenced by multiple contributing factors. These factors would include (1) the virulence of the infecting organism and persistence of bacteremia, (2) extent of local tissue destruction of the involved valve(s) and hemodynamic sequelae, (3) perivalvular extension of infection, (4) septic embolization to any organ in the systemic arterial circulation or to the lungs, as in the case of right-sided IE, and (5) the consequences of circulating immune complexes and systemic immunopathologic factors.

The diverse potential symptoms associated with IE are listed in Table 64-1. The frequency of symptoms has been approximated from numerous clinical series in both the older and more contemporary literature. Fever (>38° C) is the most common presenting symptom in up to 95% of patients, but may be absent in up to 20% of cases, particularly in elderly persons,¹⁵, the immunocompromised, patients treated with previous empirical antibiotic therapy, or patients with infections of implantable cardiac device.²⁰^,²¹ Fever defervescence usually occurs within 5 to 7 days of appropriate antibiotic therapy. Persistence of fever may indicate progressive infection with perivalvular extension such as abscess, septic embolization, an extracardiac site of infection (native or prosthetic), infected indwelling catheters or devices, inadequate antibiotic treatment of a resistant organism, or even an adverse reaction to the antibiotic therapy itself.

TABLE 64-1

Symptoms in Infective Endocarditis

SYMPTOM	PATIENTS AFFECTED (%)
Fever	80-95
Chills	40-70
Weakness	40-50
Malaise	20-40
Sweats	20-40
Anorexia	20-40
Headache	20-40
Dyspnea	20-40
Cough	20-30
Weight loss	20-30
Myalgia/arthralgia	10-30
Stroke	10-20
Confusion/delirium	10-20
Nausea/vomiting	10-20
Edema	5-15
Chest pain	5-15
Abdominal pain	5-15
Hemoptysis	5-10
Back pain	5-10

Other nonspecific constitutional symptoms of infection, such as chills, sweats, cough, headache, malaise, nausea, myalgias, and arthralgias are less common accompanying symptoms and may be noted in approximately 20% to 40% of patients. In more protracted subacute cases of IE, symptoms and signs such as anorexia, weight loss, weakness, arthralgias, and abdominal pain may also occur in 5% to 30% of patients, misleading the clinician to pursue incorrect diagnoses such as malignancy, connective tissue disease, or other chronic infection or systemic inflammatory disorder.

Symptoms of dyspnea are important to recognize because they may be indicative of a severe hemodynamic lesion, usually left-sided valvular regurgitation. Associated symptoms of orthopnea and paroxysmal nocturnal dyspnea herald the onset of heart failure. Early recognition of heart failure symptoms is imperative, as it is the most common complication of IE, has the greatest impact on prognosis, is the most frequent indication for surgical intervention, and is the most important predictor of poor outcome with surgical therapy for IE.²² Heart failure complicates the course of approximately 30% to 50% of patients with IE⁸^,¹⁶^,²³^,²⁴ and even with early surgical intervention, still doubles in-hospital mortality to nearly 25%.²⁴

A variety of chest pain syndromes can accompany IE. Pleuritic chest pain may result from septic pulmonary embolization and infarction complicating tricuspid IE. Much less common is angina pectoris related to embolization of vegetation fragments into the coronary circulation, which complicates IE in approximately 1% of the cases.²⁵ Musculoskeletal chest symptoms related to systemic infection or superimposed infectious pneumonitis also would be in the differential diagnosis.

Physical Examination

Potential findings on physical examination are delineated in Table 64-2. These data are approximated from both older and more recently reported clinical series.⁸^,¹⁶^,¹⁹^,²²^–²⁴ A definite murmur is audible in at least 80% of patients on presentation, particularly with left-sided IE. In the large International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS), the murmur was new in almost 50% of the patients.⁸ The same cohort study found that worsening of a preexisting murmur occurred in 20% of cases. The presence of a new heart murmur also is noted more frequently in patients with IE complicated by heart failure,²² and an S₃ gallop and pulmonary rales would further substantiate this diagnosis. Murmurs are detected in less than half of patients with IE complicating an implanted cardiac device²⁰ and are uncommonly heard in patients with right-sided IE. Heart murmurs associated with acute IE complicated by extensive left-sided valvular destruction with acute, severe regurgitation may also be deceptively unimpressive owing to the nature of the decompensated hemodynamics in these unstable patients. Precipitous heart failure, pulmonary edema, and cardiogenic shock are most often associated with severe acute aortic regurgitation associated with IE, less so by severe acute mitral regurgitation. Severe tricuspid regurgitation, even as an acute complication of IE, is far better tolerated.