Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis

INTRODUCTION — Infective endocarditis (IE) refers to infection of the endocardial surface of the heart; it usually refers to infection of one or more heart valves or infection of an intracardiac device.

The clinical manifestations and evaluation of adults with suspected left-sided native valve IE will be reviewed here. Issues related to right-sided native valve IE are discussed separately. (See "Right-sided native valve infective endocarditis".)

Issues related to risk factors, complications, antimicrobial therapy, surgery, and outcome of native valve IE are discussed separately:

●(See "Native valve endocarditis: Epidemiology, risk factors, and microbiology".)

●(See "Complications and outcome of infective endocarditis".)

●(See "Antimicrobial therapy of left-sided native valve endocarditis".)

●(See "Surgery for left-sided native valve infective endocarditis".)

Issues related to clinical manifestations, diagnosis, and management of prosthetic valve IE and cardiac device infections are also discussed separately:

●(See "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".)

●(See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●(See "Antimicrobial therapy of prosthetic valve endocarditis".)

●(See "Surgery for prosthetic valve endocarditis".)

RISK FACTORS — Risk factors for native valve infective endocarditis (IE) include cardiac factors (history of prior IE or pre-existing valvular or congenital heart disease), underlying conditions (such as intravenous drug use, an indwelling cardiac device or intravenous catheter, or immunosuppression), or a recent dental or surgical procedure. Issues related to risk factors for IE are discussed further separately. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology", section on 'Risk factors'.)

CLINICAL MANIFESTATIONS — The clinical manifestations of infective endocarditis (IE) are variable; IE may present as an acute, rapidly progressive infection or as a subacute or chronic disease with low-grade fever and nonspecific symptoms [1,2].

Symptoms and signs

●Symptoms – Fever is the most common symptom of IE (up to 90 percent of patients); it is often associated with chills, anorexia, and weight loss. Fever patterns in IE vary widely; their temporal patterns or severity have no diagnostic utility. Patients with IE typically have continuous bacteremia, regardless of whether fever is present. Other common symptoms of IE include malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, and dyspnea [3]. Patients with IE associated with dental infection may report tooth pain or related symptoms.

●Signs – A new or changing cardiac murmur is observed in approximately 85 percent of patients. Supportive signs include splenomegaly and cutaneous manifestations such as petechiae or splinter hemorrhages. Petechiae are observed in 20 to 40 percent of patients; they may be present on the skin (usually on the extremities) or on mucous membranes such as the palate or conjunctivae (picture 1). Splinter hemorrhages consist of nonblanching linear reddish-brown lesions under the nail bed (picture 2). However, neither their presence nor location are diagnostic of IE, as they are commonly found in otherwise normal patients [4]. (See "Auscultation of cardiac murmurs in adults".)

●Relatively uncommon manifestations highly suggestive of IE

•Janeway lesions – Nontender erythematous macules on the palms and soles (picture 3).

•Osler nodes – Tender subcutaneous violaceous nodules mostly on the pads of the fingers and toes, which may also occur on the thenar and hypothenar eminences (picture 4). Tenderness may be present a few days before appearance of the nodule.

•Roth spots – Exudative, edematous hemorrhagic lesions of the retina with pale centers.

Janeway lesions are more common in acute than subacute IE; histologically, they reflect microabscesses with neutrophil infiltration of capillaries. Osler nodes and Roth spots occur most frequently in the setting of a protracted time course of endocarditis; they probably represent the sequelae of vascular occlusion by microthrombi leading to localized immune-mediated vasculitis. Roth spots (also described as Litten spots) occur in 2 percent of patients with IE [5]. Osler nodes were commonly observed among patients with IE in the preantibiotic era but are now uncommon since IE is frequently diagnosed and treated before their development.

●Complications as initial presentation – Clinical manifestations reflecting complications of IE may be present at the time of initial presentation and/or may develop subsequently, as discussed below. When present, such findings warrant independent diagnostic evaluation, concurrent with evaluation for IE. (See 'Complications as initial presentation' below.)

Complications as initial presentation — IE is associated with a broad array of systemic complications due to septic embolization, which may be associated with localized thrombosis, bleeding, infection, and/or development of immune reactions. Clinical manifestations reflecting these complications may be present at the time of initial presentation and/or may develop subsequently (see "Complications and outcome of infective endocarditis"):

●Cardiac complications (up to 50 percent of patients) – Valve regurgitation, heart failure, and conduction abnormalities. In patients with a new diagnosis of valve regurgitation, and in patients with mitral valve prolapse and a new diagnosis of chordal rupture, IE warrants consideration even in the absence of fever.

●Neurologic complications (up to 40 percent of patients) – Embolic stroke, intracerebral hemorrhage, brain abscess, and others.

●Septic emboli (up to 25 percent of patients) – Infarction of kidneys, spleen, and other organs. In patients with concomitant right-sided endocarditis, septic pulmonary emboli may be seen (image 1). (See "Right-sided native valve infective endocarditis".)

●Metastatic infection (such as vertebral osteomyelitis, septic arthritis, splenic or psoas abscess).

●Systemic immune reactions (eg, glomerulonephritis).

Detection of the full spectrum of clinical manifestations of IE complications requires a careful, focused initial evaluation as well as serial follow-up examinations. As examples, patients with IE may present with clinical manifestations of congestive heart failure due to valvular regurgitation, focal neurologic complaints due to an embolic stroke, or back pain due to vertebral osteomyelitis. A thorough investigation of extracardiac manifestations is particularly important in the setting of Staphylococcus aureus bacteremia given the virulence of this organism. Issues related to complications of IE are discussed further separately. (See "Clinical manifestations of Staphylococcus aureus infection in adults" and "Complications and outcome of infective endocarditis".)

Laboratory and ECG findings — Routine laboratory findings in the setting of IE are relatively nonspecific; they may include elevated inflammatory markers (erythrocyte sedimentation rate and/or elevated C-reactive protein), normochromic-normocytic anemia, and positive rheumatoid factor. Hyperglobulinemia, cryoglobulinemia, circulating immune complexes, hypocomplementemia, and false-positive serologic tests for syphilis occur in some patients. Urinalysis may demonstrate microscopic hematuria, proteinuria, and/or pyuria.

IE-related immune complex-mediated glomerulonephritis (a minor diagnostic criterion for IE) is suggested by acute kidney injury along with hematuria, proteinuria, red blood cell casts, and serologic findings of hypocomplementemia, cryoglobulinemia, and/or presence of circulating immune complexes. (See 'Establishing a diagnosis of IE' below.)

Electrocardiography (ECG) may demonstrate new or evolving conduction disease (first- or second-degree atrioventricular block, bundle branch block, or complete heart block), reflecting paravalvular or myocardial extension of infection [6].

EVALUATION

When to suspect IE — The diagnosis of infective endocarditis (IE) should be suspected in patients with bacteremia due to an organism with known propensity to cause endocarditis; other important clues include fever, relevant cardiac risk factors (prior IE, history of valvular or congenital heart disease), and other predisposing conditions (intravenous drug use, indwelling cardiac device or intravenous catheter, immunosuppression, or a recent dental or surgical procedure).

History and physical examination — Clinical history should include assessment of relevant symptoms, including their nature and duration. Physical examination should include cardiac auscultation and evaluation for stigmata of IE. (See 'Symptoms and signs' above.)

Risk factors and comorbid conditions for IE should also be reviewed. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology".)

Blood cultures — At least two sets of blood cultures should be obtained from separate venipuncture sites prior to initiation of antibiotic therapy. Three or more blood culture sets are ideal for distinguishing IE from non-IE bloodstream infection in the setting of microbes that are common skin colonizers or are unusual causes of IE. (See "Detection of bacteremia: Blood cultures and other diagnostic tests".)

We obtain follow-up blood cultures 24 to 72 hours after antimicrobial therapy is begun, and repeat every one to three days until clearance of bacteremia is documented [7]. (See "Detection of bacteremia: Blood cultures and other diagnostic tests" and "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Empiric therapy'.)

Collection

●Number of blood culture sets – Blood cultures are the cornerstone of microbiological diagnosis of IE; three blood cultures sets (each set consists of one aerobic bottle and anaerobic bottle) detect 96 to 98 percent of bacteremia [3]. Two blood culture sets are often standard clinical practice; however, in the setting of suspicion for IE, it would be ideal to obtain at least three blood culture sets should be obtained from separate venipuncture sites, prior to initiation of antibiotic therapy [8,9].

In the absence of recent antimicrobial therapy, the diagnostic yield of more than three sets of blood cultures is minimal. In one series including 206 cases of IE, the initial blood culture in patients with streptococcal endocarditis was positive in 96 percent of cases, and one of the first two blood cultures was positive in 98 percent [10]. In patients with IE caused by organisms other than Streptococcus, the first blood culture was positive in 82 percent of cases, and one of the first two cultures was positive in 100 percent of cases [10].

In patients who have received recent antimicrobial therapy, additional blood cultures may be useful (two to three additional sets collected over several days). The utility of repeat blood cultures depends on the underlying clinical circumstances. For example, many patients with S. aureus IE have positive blood cultures for several days after initiation of antimicrobial therapy, whereas patients with IE due to highly susceptible strains of bacteria such as viridans group streptococci may have negative blood cultures after a few doses of antimicrobial therapy.

●Timing – Patients with IE typically have continuous bacteremia; therefore, blood cultures may be collected at any time and need not necessarily be obtained at the time of fever or chills [11].

●Volume – The volume of blood for each blood culture set in adults is 20 mL (10 mL into each bottle).

Additional issues related to collecting blood cultures for detection of bacteremia are discussed further separately. (See "Detection of bacteremia: Blood cultures and other diagnostic tests".)

Interpretation

●Time to positivity – Most clinically significant bacteremias are detected within 48 hours; common and fastidious pathogens (such as members of the HACEK group) are usually detected within five days of incubation with modern automated blood culture detection systems.

●Typical organisms – Typical microorganisms consistent with IE include S. aureus, S. lugdunensis, E. faecalis, all streptococcal species (except for S. pneumoniae and S. pyogenes), Granulicatella and Abiotrophia spp., Gemella spp., and HACEK group organisms (Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae).

The likelihood of IE is greater in the setting of bacteremia due to Streptococcus sanguis than Streptococcus milleri [12]. Bacteremia due to group G Streptococcus is more frequently associated with IE than bacteremia due to group A or C streptococci [13]. Bacteremia due to Enterococcus faecalis has been more frequently associated with IE than bacteremia due to other enterococcal species [14].

●Organisms in the setting of intracardiac prosthetic material – Additional microbes should be considered as typical pathogens in the setting of intracardiac prosthetic material: coagulase-negative staphylococci, Corynebacterium striatum and C. jeikeium, Serratia marcescens, Pseudomonas aeruginosa, Cutibacterium acnes, nontuberculous mycobacteria (especially M. chimaera), and Candida spp. The microbiology of IE is discussed further separately. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology", section on 'Microbiology' and "Infections due to the Streptococcus anginosus (Streptococcus milleri) group" and "Group C and group G streptococcal infection".)

●Distinguishing between pathogenicity and contamination – Organisms for which it can be difficult to distinguish between pathogenicity and contamination include Cutibacterium (formerly Propionibacterium) acnes, Corynebacterium species, Bacillus species, and coagulase-negative staphylococci. In general, the likelihood of pathogenicity is increased if the organism is observed in multiple blood cultures obtained by independent venipunctures. Recovery of these organisms from a single blood culture or a minority of blood culture bottles is more likely to reflect a false-positive result. (See "Detection of bacteremia: Blood cultures and other diagnostic tests", section on 'Assessing clinical significance'.)

Cardiac imaging

Echocardiography as primary modality — Echocardiography should be performed in all patients with suspected IE as soon as possible after the diagnosis of IE is suspected (algorithm 1 and algorithm 2) [1,15-17].

Echocardiography is warranted even for patients with an associated condition that requires a protracted course of antimicrobial therapy (such as vertebral osteomyelitis), since documenting the presence or absence of vegetation is important for determination of subsequent follow-up. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Follow up'.)

Choosing between TTE and TEE — In general, transthoracic echocardiography (TTE) is the first diagnostic test for patients with suspected IE. However, transesophageal echocardiography (TEE) has higher sensitivity than TTE and is better for detection of cardiac complications. Data obtained by TTE and TEE are complementary, so both studies are useful in most patients; however, it is reasonable to forgo TTE and proceed to TEE for patients with a prior valvular abnormality (including previous endocarditis) or limited transthoracic windows (eg, due to obesity, chest wall deformity, or mechanical ventilation).

●TTE

•Diagnostic scope – Echocardiography is considered positive for IE in the setting of vegetation or abscess. Other findings, such as intra-cardiac fistula and valve leaflet perforation, also reflect IE but are more challenging to confirm by TTE (movie 1 and movie 2 and movie 3 and movie 4).

Echocardiography is also useful for evaluating valvular dysfunction, assessing hemodynamic severity of the valve lesion, assessing underlying ventricular function, and detecting associated abnormalities such as shunts. In addition, echocardiography is an important tool for follow-up evaluation of patients with persistent or recurrent bacteremia or other clinical deterioration. (See "Role of echocardiography in infective endocarditis".)

•Sensitivity and specificity – The sensitivity of TTE is modest (up to 75 percent); the specificity approaches 100 percent [18]. False-negative results may be obtained if vegetations are small and/or if vegetations have embolized. Thus, the absence of vegetation on TTE does not preclude the diagnosis of IE, although the presence of normal valve morphology and function on TTE substantially reduces the likelihood of IE [19]. In one study including 134 patients with suspected IE, 96 percent of patients with normal valves and no vegetation on TTE also had a negative TEE [20].

●TEE

•Diagnostic scope – In addition to identification of vegetations, TEE allows evaluation of the severity of valve dysfunction, assessment of left and right ventricular systolic function, and estimation of pulmonary pressures, and it may detect complications of endocarditis.

•Indications – TEE is warranted in the following circumstances (algorithm 1 and algorithm 2) [1,3,21,22]:

-TTE without evidence of endocarditis, or TTE technically inadequate, with clinical suspicion for IE (bacteremia due to an organism known to be a common cause of IE, particularly S. aureus, and/or multiple minor criteria for endocarditis) (see '2023 Duke-ISCVID criteria' below)

-TTE with valve vegetation, with concern for presence of intracardiac complications such as paravalvular abscess (risk factors include new conduction delay on ECG, aortic valve endocarditis, and persistent bacteremia or fever despite appropriate antimicrobial therapy)

-TTE with valve vegetation as well as significant valvular regurgitation, to determine need for surgery

•Sensitivity and specificity – TEE has a sensitivity of >90 percent for detection of valvular vegetation and is superior to TTE for detection of cardiac complications such as abscess, leaflet perforation, and aortic pseudoaneurysm or intracardiac fistula. Therefore, TEE is useful in most cases, even if TTE was sufficient to establish the diagnosis of IE [23,24]. Of note, the specificity of TEE is not 100 percent; false-positive findings can occur with cardiac tumors, mural thrombi, or fibrous strands on the aortic valve [3]. (See "Role of echocardiography in infective endocarditis".)

●Negative echocardiography but clinical suspicion for IE persists – Patients with a negative TEE for whom the clinical suspicion for IE remains high (eg, patients who are at high risk for IE and have persistent bacteremia or fever without another identifiable source, and/or multiple minor criteria for IE) should undergo repeat TEE approximately one week later [1,25]. Repeat TEE is also warranted after an initial positive TEE if clinical features suggest new development of an intracardiac complication [1].

If TTE and TEE are both nondiagnostic, additional imaging tools include cardiac computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET)/CT.

Emerging imaging modalities — Emerging modalities include cardiac CT and FDG PET/CT:

●Cardiac CT – Cardiac CT may be helpful for cases in which definitive evidence of IE and its complications cannot be demonstrated with TEE, and/or for planning surgery in patients with extravalvular complications. Cardiac CT has lower sensitivity than echocardiography for vegetations [26] but appears to have higher sensitivity for detection of paravalvular abscess and pseudoaneurysm [27-30]. Cardiac CT may be more informative than TEE when TEE is limited by artifact [30-33].

If clinically warranted, CT imaging of the brain and/or torso may be obtained at the same time to evaluate for evidence of systemic embolization [34]. (See 'Additional evaluation for IE source or complications' below.)

●FDG PET/CT – FDG PET/CT can identify infection of native valves and paravalvular areas, as well as extracardiac sites of infection [35,36]. The sensitivity of FDG PET/CT for diagnosis of native valve IE is lower than for prosthetic valve IE; this is likely due to fibrosis in native valve IE, compared with inflammation in prosthetic valve IE [2,37].

Data on use of FDG PET/CT in the setting of suspected native valve IE in include:

•In a meta-analysis including 13 studies and 537 patients who underwent FDG PET/CT, the sensitivity and specificity for diagnosis of endocarditis were 77 and 78 percent, respectively [38].

•In one study including 115 patients with suspected native valve IE, when FDG PET/CT evidence of distal septic emboli was used as a minor criterion, 11 out of 26 cases of "possible" were re-classified to "definite" native valve IE [37].

•In one study including 70 patients with suspected native valve IE, FDG PET/CT led to a modification in management (mostly antibiotic treatment) in 31 percent of cases [39].

•Extracardiac sites of infection may be detected by FDG PET/CT in 40 to 60 percent of cases of definite IE [35,37,40].

•In one study of 140 patients with suspected native and prosthetic valve IE, a previously unsuspected portal of entry was detected in 8 percent of cases [40].

Additional evaluation for IE source or complications — Additional evaluation for patients with suspected infective endocarditis (IE) includes ECG, chest radiography, other radiographic imaging tailored to clinical manifestations, and dental evaluation.

●Electrocardiography – Baseline ECG should be performed as part of the initial evaluation for all patients with suspected IE, with subsequent telemetry monitoring or serial ECGs. The presence of heart block or conduction delay (which may manifest initially as a prolonged PR interval) may provide an important clue to paravalvular extension of infection to the valve annulus and adjacent septum (which should prompt further evaluation with ECG as discussed below). In addition, the presence of findings consistent with ischemia or infarction may suggest the presence of emboli to the coronary circulation. (See "ECG tutorial: Basic principles of ECG analysis".)

●Chest radiography – Chest radiography is warranted to evaluate for presence of septic pulmonary emboli (image 1), infiltrate (with or without cavitation), congestive heart failure, and potential alternative causes of fever and systemic symptoms.

●Computed tomography – CT of the torso (chest, abdomen, and pelvis) is useful to evaluate for sites of metastatic infection (such as splenic infarct, renal infarcts, psoas abscess, or other sites of infection) that may warrant localized drainage [1,41]. However, the decision to pursue this imaging should be guided by a careful history and clinical assessment. In one study including more than 500 patients with possible or definite IE who underwent thoracoabdominal CT, the diagnosis of IE was upgraded from possible to definite in only 0.8 percent of cases; acute kidney injury within five days of imaging was observed in 15 percent of patients [42].

●Additional radiographic imaging – Additional radiographic imaging to evaluate for complications of IE should be tailored to findings on history and physical examination [1]. As examples, patients with back pain should be evaluated for the possibility of vertebral osteomyelitis with imaging studies (see "Vertebral osteomyelitis and discitis in adults"), and patients with headache, neurologic deficits, or meningeal signs should be evaluated with head magnetic resonance imaging (MRI) for neurologic complications (including intracranial mycotic aneurysm or central nervous system bleeding). (See "Overview of infected (mycotic) arterial aneurysm".)

Routine brain imaging with CT or MRI is not mandatory in the absence of focal neurologic signs or symptoms. However, since asymptomatic cerebral infarcts are relatively common in patients with IE, their presence can be diagnostically important (as signs of systemic emboli) if they are detected in patients with possible IE based on other findings [1,40,43,44]. As an example, in one study including 53 patients, early use of cerebral MRI led to upgraded classification of IE to definite or possible in one-third of cases [40].

For patients with IE in the absence of neurologic signs or symptoms, brain imaging may be useful if cardiac surgery is being considered or planned. In a systematic review and meta-analysis including 21 studies (mostly retrospective) and more than 2100 patients with suspected or confirmed IE who underwent brain MRI, acute ischemic lesions or microbleeds were observed in more than half of cases; hemorrhagic lesions, abscess, meningitis, and intracranial mycotic aneurysms were observed less commonly [45]. Similarly, in a retrospective study including 155 patients with IE in the absence of neurologic signs or symptoms, cerebral imaging demonstrated a new surgical indication (defined as a cerebral embolic event in the presence of a left-sided vegetation >10mm) in 19 percent of cases [46].

●Dental evaluation – Patients with IE should undergo a thorough dental evaluation; the examination should focus on periodontal inflammation, pocketing around teeth, and caries that may result in pulpal infection and subsequent abscess [1]. All active sources of oral infection should be eradicated, and patients should be counseled regarding the importance of daily dental hygiene with serial dental evaluation. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Follow up'.)

Evaluation of resected valve — The clinical diagnosis of IE may be established via pathologic criteria, which include presence of microorganisms or histopathologic findings of active endocarditis. Culture, staining, immunologic techniques, polymerase chain reaction (PCR), or other nucleic acid-based tests of resected heart valves may be useful for cases in which blood cultures are negative. However, routine use of these tools is not warranted in the absence of clinical suspicion for IE because they may be associated with false-positive results. In one study including 1030 valves removed at surgery, cultures were positive in 39 percent of patients that met Duke criteria for IE and in 28 percent of patients without other criteria for IE [47].

Issues related to molecular testing of excised valve are discussed further separately. (See "Blood culture-negative endocarditis: Epidemiology, microbiology, and diagnosis", section on 'Further evaluation'.)

ESTABLISHING A DIAGNOSIS OF IE — The diagnosis of infective endocarditis (IE) is established based on clinical manifestations, blood cultures (or other microbiologic data), and cardiac imaging [3]. The diagnosis of IE requires (1) identification of the infecting pathogen by culture, serologic testing, or molecular testing and (2) cardiac imaging to identify a valvular vegetation, paravalvular abscess, or other structural complication of infection. The accepted criteria for diagnosis of IE are the 2023 Duke-International Society for Cardiovascular Infectious Disease (ISCVID) criteria [48,49], which were updated from the 2000 modified Duke criteria [49]. These criteria are summarized below and in the tables (table 1 and table 2).

2023 Duke-ISCVID criteria — The 2023 Duke-International Society for Cardiovascular Infectious Disease (ISCVID) criteria for IE [48] were updated from the 2000 modified Duke criteria [49,50]. The 2023 European Society for Cardiology (ESC) Guidelines for the Management of Endocarditis has an updated schema for the diagnosis of IE [2], which is similar to that of the Duke-ISCVID criteria.

The criteria should be used as a diagnostic guide together with clinical judgment and must be interpreted in the context of the pretest probability for IE.

IE definitions

Definite IE — Definite IE is established if pathologic criteria (either microbiologic or histopathologic criteria) or clinical criteria outlined below are met. Most patients with suspected IE do not meet pathologic criteria and the diagnosis often relies on clinical features (table 1).

●Pathologic criteria (either microbiologic or histopathologic criteria):

•Microbiologic criteria – Microorganisms identified in the context of clinical signs of active endocarditis:

-In a vegetation

-From cardiac tissue

-From an explanted prosthetic valve or sewing ring

-From an ascending aortic graft (with concomitant evidence of valve involvement)

-From an endovascular cardiac implantable electronic device (CIED)

-From an embolus

•Histopathologic criteria – Histopathologic findings of active endocarditis identified (may be acute or subacute/chronic):

-In or on a vegetation

-From cardiac tissue

-From an explanted prosthetic valve or sewing ring

-From an ascending aortic graft (with concomitant evidence of valve involvement)

-From a CIED

-From an embolus

●Clinical criteria (see 'Clinical criteria' below)

•Two major clinical criteria

•One major and three minor clinical criteria

•Five minor clinical criteria

Possible IE — Possible IE is defined as either of the following (table 1):

●One major and one minor clinical criteria

●Three minor clinical criteria

Rejected IE — The diagnosis of IE may be rejected if any of the following is present (table 1):

●A firm alternate diagnosis explaining signs and symptoms is made

●Lack of recurrence despite antibiotic therapy for <4 days

●No pathologic evidence of infective endocarditis is found at surgery or autopsy after antibiotic therapy for four days or less

●Clinical criteria for possible or definite infective endocarditis are not met

Clinical criteria — Many patients with suspected IE do not meet sufficient criteria for definite IE. In the absence of pathologic criteria, clinical criteria (major and minor) for the diagnosis of IE are summarized below and in the table (table 2).

Major criteria — Major clinical criteria include (table 2):

●Microbiologic criteria (either positive blood cultures or positive laboratory test)

•Positive blood cultures (one of the following):

-Microorganisms that commonly cause IE, isolated from two or more separate blood culture sets

-Microorganisms that occasionally or rarely cause IE, isolated from three or more separate blood culture sets

•Positive laboratory test (one of the following):

-Positive PCR or other nucleic acid-based technique from blood for Coxiella burnetii, Bartonella spp., or Tropheryma whipplei

-Coxiella burnetii antiphase I immunoglobulin G (IgG) antibody titer >1:800 or Coxiella burnetii isolated from a single blood culture

-Indirect immunofluorescence assays for detection of IgM and IgG antibodies to Bartonella henselae or Bartonella quintana, with IgG titer ≥1:800

●Imaging criteria (either of the following):

•Echocardiography and/or cardiac computed tomography (CT) imaging (any of the following):

-Echocardiography and/or cardiac CT demonstrating vegetation, valvular/leaflet perforation, valvular/leaflet aneurysm, abscess, pseudoaneurysm, or intracardiac fistula

-Significant new valvular regurgitation on echocardiography, compared with previous imaging; worsening or changing of pre-existing regurgitation is not sufficient

-New partial dehiscence of prosthetic valve (compared with previous imaging)

•[¹⁸F]-FDG PET/CT imaging

-Abnormal metabolic activity involving a native or prosthetic valve (at least three months after implantation), ascending aortic graft (with concomitant evidence of valve involvement), intracardiac device leads, or other prosthetic material

●Surgical major criterion

•Evidence of IE observed by direct inspection during cardiac surgery, in the absence of major microbiologic or imaging criteria, and in the absence of pathologic (microbiologic or histologic) criteria

Minor criteria — Minor clinical criteria include (table 2):

●Predisposition

•Previous history of IE

•Prosthetic valve

•Previous valve repair

•Congenital heart disease

•More than mild regurgitation or stenosis (of any etiology)  

•Endovascular CIED

•Hypertrophic obstructive cardiomyopathy

•Injection drug use

●Fever

•Temperature ≥38.0°C (100.4°F)

●Vascular phenomena

•Clinical or radiographic evidence of arterial emboli, septic pulmonary infarcts, cerebral or splenic abscess, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions, purulent purpura

●Immunologic phenomena

•Positive rheumatoid factor, Osler nodes, Roth spots, or immune complex-mediated glomerulonephritis

●Microbiologic evidence (not meeting major criteria)

•Positive blood cultures for a microorganism consistent with IE but not meeting requirements for major criteria

•Positive culture, PCR, or other nucleic acid-based test (amplicon or shotgun sequencing, in situ hybridization) for an organism consistent with IE from a sterile body site other than cardiac tissue, cardiac prosthesis, or embolus; or a single finding of a skin bacterium by PCR on a valve or wire without additional clinical or microbiologic supporting evidence

●Imaging

•Abnormal metabolic activity detected by [¹⁸F]-FDG PET/CT within three months of implantation of prosthetic valve, ascending aortic graft (with concomitant evidence of valve involvement), intracardiac device leads or other prosthetic material

●Physical examination (if echocardiography is not available)

•New valvular regurgitation identified on auscultation (based on expert opinion); worsening or changing of pre-existing murmur not sufficient

Basis for Duke criteria revision — The 2023 Duke-ISCVID criteria [48] were updated from the 2000 modified Duke criteria [49]; they were developed to reflect in the epidemiology of IE along with the emergence of newer imaging and microbiologic diagnostic tools. Examples of changes in epidemiology and diagnostics which inform the 2023 Duke-ISCVID criteria, particularly with respect to native valve IE include:

●Changes in our understanding of the epidemiology of IE –

•E. faecalis – In the 2023 Duke-ISCVID criteria, E. faecalis is classified as a typical cause of IE regardless of acquisition (community- or healthcare-associated) and regardless of whether there is a primary extracardiac focus of infection. In the 2000 modified Duke criteria, E. faecalis was included as a major criterion only if community-acquired and in the absence of a primary focus.

This change is supported by a prospective study including more than 340 patients with E. faecalis bacteremia evaluated with echocardiography; consideration of E. faecalis as a "typical" endocarditis pathogen (regardless of the place of acquisition or the portal of entry) improved the sensitivity for identification of definite endocarditis from 70 to 96 percent [51]. These findings suggest in patients with E. faecalis bacteremia, the potential for IE is significant (even in the setting of healthcare acquisition or extracardiac focus).

•Other organisms – Additional organisms considered typical causes of IE added as major microbiologic criteria include S. lugdunensis, all streptococci except S. pneumoniae and S. pyogenes, Granulicatella spp, Abiotrophia spp, and Gemella spp.

For intracardiac prosthetic material, organisms added as major microbiological criteria include coagulase-negative staphylococci, Corynebacterium striatum, Corynebacterium jeikeium, Serratia marcescens, Pseudomonas aeruginosa, Cutibacterium acnes, nontuberculous mycobacteria, and Candida spp.

●Advances in microbiologic diagnostic testing – Advances in microbiologic diagnostic testing include PCR of tissue or other sterile body site (such as amplicon or metagenomic sequencing and in situ hybridization), in addition to blood culture and serology.

New major microbiologic criteria include:

•Blood PCR or amplicon/metagenomic sequencing identifying Coxiella burnetii, Bartonella spp, or Tropheryma whipplei

•IFA for detection of antibodies to B. henselae or B. quintana, with IgG titer >1:800

●Advances in imaging – Advances in imaging include improved understanding of the diagnostic utility of cardiac CT and FDG PET/CT for detection of IE, which were added as major imaging criteria. (See 'Emerging imaging modalities' above.)

●Value of operative findings – It has been recognized that intraoperative inspection of cardiac pathology is valuable, particularly for situations in which supportive histopathologic, microbiologic, or imaging data are not available.

Validation of Duke criteria — The 2023 Duke-ISCVID criteria have undergone validation studies using an adjudication panel of experts to determine the diagnosis of IE as the reference standard:

●In a study including 595 patients with suspected IE in Amsterdam, the 2023 Duke-ISCVID Criteria had higher sensitivity for the diagnosis of IE than the modified Duke criteria (2000) or the ESC 2015 criteria (84, 75, and 80 percent, respectively); the specificity was similar among all three criteria (94 percent) [52].

●In a study including 1194 patients in France, the sensitivity of the 2023 Duke-ISCVID criteria was higher than the modified Duke criteria (2000) and the ESC 2015 criteria (98, 93, and 95 percent, respectively) [53]. However, in this study the specificities were low for all of the criteria (46, 61, and 61 percent); this is due in part to the addition of positive culture or PCR from a percutaneously extracted CIED, findings which were often not accepted as major criteria for definite IE by the reference adjudicators.

Culture-negative endocarditis — Culture-negative IE is defined as endocarditis with no definitive microbiologic etiology following inoculation of at least three independently obtained blood samples in a standard blood-culture system, with negative cultures after five days of incubation and subculturing.

There are three main categories of culture-negative IE: IE due to bacterial pathogens whose growth in culture is prevented by antecedent antimicrobial therapy; IE due to microorganisms with fastidious growth characteristics in vitro (such as Gemella, Granulicatella, and Abiotrophia species); and IE due to intracellular bacteria that cannot be cultured from blood using standard microbiologic testing methods [54].

Culture-negative IE should be suspected in patients with negative blood cultures and persistent fever with one or more clinical findings consistent with IE (eg, stroke or other manifestations of emboli). Culture-negative IE should also be suspected in patients with vegetation on echocardiogram and no clear microbiologic diagnosis. Some causes of culture-negative IE may be identified via serology or PCR; these include Coxiella burnetii, Bartonella spp., Chlamydia spp., Tropheryma whipplei, Legionella spp., Mycoplasma, and Brucella [48].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for endocarditis is broad and should be considered based on two clinical categories: presence of bacteremia in the absence of valvular vegetation and presence of valvular vegetation(s) in the absence of bacteremia.

Patients with bacteremia in the absence of evidence for valvular vegetation should be evaluated for alternative causes of bacteremia (which may coexist with IE), including:

●Intravascular catheter infection – Catheter-related infection should be suspected when bacteremia occurs in the setting of a central venous catheter with no other apparent source. The diagnosis is established based on evaluation of samples drawn from the catheter and a peripheral vein. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●Cardiac device infection – Cardiac device infection should be suspected in the setting of an implanted device with overlying inflammation. Echocardiography is warranted to evaluate for device-related endocarditis. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Forms of infection'.)

●Prosthetic joint infection – Prosthetic joint infection should be suspected in the setting of a prosthetic joint with local erythema or tenderness. Evaluation of joint fluid or tissue is required to establish the diagnosis. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

●Hematogenous osteomyelitis – Hematogenous osteomyelitis should be suspected in the setting of focal pain at an involved site. Evaluation with radiographic imaging is warranted; the involved pathogen may be established by bone biopsy. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

●Septic thrombophlebitis – Septic thrombophlebitis should be suspected in the setting of persistent bacteremia in the presence of an intravascular catheter or prior intravascular catheter. Patients may present with erythema, edema, palpable cord, or drainage from the site of the involved vessel. (See "Catheter-related septic thrombophlebitis".)

●Infected arterial aneurysm – An infected arterial aneurysm should be suspected in patients with a risk factor for arterial injury (such as recent vascular procedure, history of endocarditis), pre-existing aneurysm, or presence of a vascular graft. (See "Overview of infected (mycotic) arterial aneurysm".)

Patients with valvular vegetation(s) or arterial emboli in the absence of bacteremia may have culture-negative endocarditis or sterile vegetation(s) (marantic endocarditis or Libman-Sachs endocarditis) due to a noninfectious etiology or antiphospholipid syndrome. (See "Diagnosis of antiphospholipid syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of infective endocarditis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Endocarditis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition and risk factors − Native valve infective endocarditis (IE) refers to infection of the endocardial surface of the heart; it usually refers to infection of one or more heart valves. Risk factors for IE include cardiac factors (history of prior IE or history of valvular or congenital heart disease) and noncardiac factors (intravenous drug use, indwelling intravenous catheter, immunosuppression, or a recent dental or surgical procedure). (See 'Risk factors' above.)

●Clinical manifestations – The clinical manifestations of IE are highly variable; IE may present as an acute, rapidly progressive infection or as a subacute or chronic disease with low-grade fever and nonspecific symptoms. Fever is the most common symptom of IE (up to 90 percent of cases); it is often associated with chills, anorexia, and weight loss. Other symptoms of IE include malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, dyspnea, cough, and pleuritic pain. Cardiac murmurs are observed in approximately 85 percent of patients. Supportive signs include cutaneous manifestations such as petechiae (picture 1), splinter hemorrhages (picture 2), Janeway lesions, or Osler nodes. (See 'Clinical manifestations' above.)

●Complications – IE is associated with a broad array of systemic complications; these include cardiac and neurologic complications, septic emboli, metastatic infection, and systemic immune reactions. Clinical manifestations reflecting these complications may be present at the time of initial presentation and/or may develop subsequently. Clinical manifestations of a complication of IE warrant independent diagnostic evaluation, concurrent with evaluation for IE. (See 'Complications as initial presentation' above.)

●Diagnostic approach

•Clinical suspicion – The diagnosis of IE should be suspected in patients with bacteremia due to an organism with known propensity to cause endocarditis; other important clues include fever, relevant cardiac risk factors (prior IE, history of valvular, or congenital heart disease), and other predisposing conditions (intravenous drug use, indwelling intravenous lines, immunosuppression, or a recent dental or surgical procedure). (See 'When to suspect IE' above.)

•Establishing a diagnosis – The diagnosis of IE is established based on clinical manifestations, blood cultures (or other microbiologic data), and echocardiography (additional imaging such as cardiac CT or FDG PET/CT may be useful if the transesophageal echocardiography [TEE] is nondiagnostic and clinical suspicion persists). The accepted criteria for diagnosis of IE are the 2023 Duke-International Society for Cardiovascular Infectious Disease (ISCVID) criteria (table 1 and table 2). (See 'Establishing a diagnosis of IE' above.)

●Blood cultures: Collection and interpretation

•Obtaining blood cultures and empiric treatment – At least two sets of blood cultures should be obtained from separate venipuncture sites prior to initiation of antibiotic therapy. (See 'Blood cultures' above.)

•Typical microorganisms (see 'Interpretation' above)

-Typical microorganisms consistent with IE include S. aureus, S. lugdunensis, E. faecalis, all streptococcal species (except for S. pneumoniae and S. pyogenes), Granulicatella and Abiotrophia spp., Gemella spp., and HACEK group organisms (Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae).

-In the setting of intracardiac prosthetic material, additional microbes should be considered as typical pathogens: coagulase-negative staphylococci, Corynebacterium striatum and C. jeikeium, Serratia marcescens, Pseudomonas aeruginosa, Cutibacterium acnes, nontuberculous mycobacteria (especially M. chimaera), and Candida spp. The microbiology of IE is discussed further separately.

•Culture-negative IE – Culture-negative IE should be suspected in patients with negative blood cultures and persistent fever with one or more clinical findings consistent with infective endocarditis (eg, stroke or other manifestations of emboli). Culture-negative IE should also be suspected in patients with vegetation on echocardiogram and no clear microbiologic diagnosis. Serologies and polymerase chain reaction (PCR) of excised valves can be used to investigate for infectious causes of culture-negative IE. (See 'Culture-negative endocarditis' above.)

●Cardiac imaging

•Echocardiography should be performed in patients with suspected IE (algorithm 1 and algorithm 2). In general, transthoracic echocardiography (TTE) is the first diagnostic test for patients with suspected IE. TEE has higher sensitivity than TTE and is better for detection of cardiac complications such as abscess, leaflet perforation, and pseudoaneurysm. In some circumstances, it is reasonable to forgo TTE and proceed to TEE. (See 'Echocardiography as primary modality' above.)

•In the setting of nondiagnostic TEE and persistent suspicion for IE, additional imaging tools include cardiac CT and FDG PET/CT. (See 'Emerging imaging modalities' above.)

●Additional evaluation – Additional evaluation for patients with suspected IE includes ECG, chest radiography, other radiographic imaging tailored to clinical manifestations and dental evaluation. (See 'Additional evaluation for IE source or complications' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Vance G Fowler, Jr, MD, who contributed to earlier versions of this topic review.