Complications and outcome of infective endocarditis

INTRODUCTION — Infective endocarditis (IE) is associated with a broad array of complications. The likelihood of complication(s) depends on several factors including the infecting pathogen, duration of illness prior to therapy, and underlying comorbidities [1]. Complications can occur before, during, and after completion of therapy.

It can be difficult to assess the true incidence of complications since case series are frequently retrospective. In one review including 223 episodes of IE, 57 percent of patients had one complication, 26 percent had two, 8 percent had three, 6 percent had four, 1 percent had five, and 1 percent had six or more complications [2].

Issues related to complications and outcome of IE will be reviewed here. Indications for surgery and timing of surgery in patients with complications of IE are discussed further separately. (See "Surgery for left-sided native valve infective endocarditis" and "Surgery for prosthetic valve endocarditis".)

Other issues related to IE are discussed separately. (See related topics.)

COMPLICATIONS OF ENDOCARDITIS — Complications of infective endocarditis (IE) include cardiac, metastatic, neurologic, renal, musculoskeletal, and pulmonary complications as well as complications related to systemic infection (including embolization, metastatic infection, and mycotic aneurysm). More than one complication can occur simultaneously.

Complications can also be considered based on pathogenesis (ie, embolic [such as cerebral infarct], local spread of infection [such as heart valve destruction], metastatic infection [such as vertebral osteomyelitis], and immune-mediated damage [such as glomerulonephritis]).

IE due to Staphylococcus aureus is associated with complications more frequently than other pathogens (stroke 21 versus 14 percent, systemic emboli 27 versus 18 percent, persistent bacteremia 17 versus 5 percent, and in-hospital mortality 22 versus 14 percent) [3].

Cardiac complications — Cardiac complications are the most common complications in IE; they occur in up to half of patients [4].

Heart failure — Heart failure is the most common cause of death due to IE in the modern era. The correlation between heart failure and mortality depends on several factors including the valve involved (aortic valve involvement is more likely to cause heart failure than mitral valve involvement), the pathogen involved (S. aureus infection increases the likelihood of heart failure), and whether the patient undergoes surgery for valve repair or replacement. Heart failure is the most common reason for cardiac surgery in patients with IE; indications for surgery in patients with cardiac complications are discussed further separately. (See "Surgery for left-sided native valve infective endocarditis" and "Surgery for prosthetic valve endocarditis".)

The usual cause of heart failure in patients with IE is valvular insufficiency resulting from infection-induced valvular damage. Rarely, embolization of fragments of valvular vegetations into the coronary arteries or obstruction of the coronary ostia by vegetation or abscess can cause acute myocardial infarction and subsequent heart failure [4].

Perivalvular abscess — Perivalvular abscess should be suspected in the setting of conduction abnormalities on electrocardiogram (ECG) and/or persistent bacteremia or fever despite appropriate antimicrobial therapy [5]. The reported incidence of perivalvular abscess among patients with IE is 30 to 40 percent [6-8]. The aortic valve and its adjacent annulus are more susceptible to abscess formation and associated complications than the mitral valve and annulus [6-8]. This was illustrated in an autopsy study including 95 patients with native valve endocarditis; annular extension of infection was more common in patients with aortic valve compared with mitral valve endocarditis (41 versus 6 percent) [6].

Perivalvular abscesses can extend into adjacent cardiac conduction tissues, leading to heart block. Involvement of the conducting system is most common in the setting of aortic valve infection, especially when there is involvement of the valve ring between the right and non-coronary cusp; this anatomic site overlies the intraventricular septum that contains the proximal ventricular conduction system. Rarely, perivalvular infection can result in extrinsic coronary compression and can cause acute coronary syndrome [9]. (See "Diagnosis of acute myocardial infarction".)

Perivalvular abscess is associated with increased risk of systemic embolization and death. In one study including 73 patients with IE, the embolization rate was approximately twice as high among patients with perivalvular abscess (64 versus 30 percent) [7]. Another study including 118 patients with IE noted higher mortality among patients with perivalvular abscess (23 versus 14 percent) [8]. In addition, the presence of moderate or severe regurgitation is associated with higher mortality rate [10].

Data are conflicting regarding correlation between vegetation size and risk for perivalvular abscess. Large vegetation size had been implicated as a risk factor for perivalvular abscess in some series, although subsequent studies have shown no correlation [7,11]. Patients with IE involving congenital bicuspid aortic valves appear to be more prone to perivalvular complications than those with IE involving tricuspid aortic valves [12]. Injection drug use may be another risk factor for perivalvular abscess [7].

Transesophageal echocardiography (TEE) is more sensitive for detection of myocardial abscess than transthoracic echocardiography (TTE) [13]. In one study including 43 patients with perivalvular abscess documented at surgery or autopsy, the sensitivity, specificity, and positive and negative predictive values of TEE were 87, 95, 91, and 92 percent, respectively [8]. The sensitivity of TTE was much lower (28 percent), although the specificity was 99 percent. While TEE is more sensitive than TTE for detecting abscess, even TEE may miss abscess in difficult imaging situations where calcification, for example of the mitral annulus, obscures perivalvular tissues. Also, abscesses are more difficult to detect before they cavitate, and repeat TEE may be required if suspicion remains high. (See "Role of echocardiography in infective endocarditis", section on 'Perivalvular abscess or fistula'.)

Other cardiac complications — Pericarditis (suppurative or nonsuppurative) can cause chest pain or cardiac tamponade [14,15]. (See "Purulent pericarditis" and "Acute pericarditis: Clinical presentation and diagnosis".)

Intracardiac fistula (eg, aorta-atrial or aorta-ventricular) may develop due to extension of infection from the valve to adjacent myocardium. Rarely, this can lead to development of an aneurysm, aortic dissection, or myocardial perforation [16,17]. In one study including 4681 episodes of IE, the incidence of fistulous intracardiac complications was 1.6 percent [18].

Metastatic infection — Forms of metastatic infection include embolization, metastatic abscess, and mycotic aneurysm.

Septic embolization — General issues related to embolization in patients with IE will be reviewed here; issues related to embolization in patients with IE who undergo surgery are discussed separately, as are issues related to antithrombotic therapy. (See "Surgery for prosthetic valve endocarditis" and "Antithrombotic therapy in patients with infective endocarditis" and "Surgery for left-sided native valve infective endocarditis", section on 'Vegetation characteristics and risk of embolization'.)

Embolization with clinical sequelae has been described in 13 to 44 percent of patients with IE; in most cases, embolization occurs prior to clinical presentation but can occur after initiation of antimicrobial therapy [19-21]. Systemic embolization most commonly occurs in left-sided IE; pulmonic embolization most commonly occurs in right-sided IE. Systemic embolization can also occur in patients with right-sided IE and right-to-left shunt (for example, through a patent foramen ovale) [22].

Emboli can occlude or damage virtually any vessel in the systemic or pulmonary arterial circulation [13]. As a result, embolization can cause:

●Stroke

●Paralysis (due to embolic infarction of either the brain or spinal cord)

●Blindness (due to embolism or due to endophthalmitis as a result of bacteremic seeding)

●Ischemia of the extremities

●Splenic or renal infarction

●Pulmonary embolism

●Acute myocardial infarction

Endocarditis should be considered as a possible etiology in patients who present with signs or symptoms of systemic arterial embolization. Most patients with acute stroke do not have endocarditis, although the likelihood of IE is increased in relatively young patients and in patients with both cerebral and systemic arterial embolization [23,24].

Risk factors — Risk factors for embolization include presence of left-sided vegetation, large vegetation size, microbiology, presence of antiphospholipid antibodies, age, diabetes, atrial fibrillation, and embolization prior to initiation of antibiotics [25-32]:

●Left-sided vegetation – Embolization with clinical sequelae occurs more frequently in patients with left-sided than right-sided vegetations [26] and more frequently with mitral vegetations than aortic vegetations [27]. In one review including 281 patients with suspected IE, the incidence of embolic events was greater with mitral than aortic valve vegetations (25 versus 10 percent) [27]. The risk was highest among patients with a vegetation on the anterior mitral leaflet (37 percent), suggesting that the mechanical effects of abrupt leaflet excursion may contribute to the risk of embolization [26].

●Large vegetation size – One study including 384 patients with IE noted that vegetation size >10 mm and severe mobility of the vegetation were predictors of new embolic events, even after adjustment for pathogen type. Vegetation size >15 mm was a predictor of one-year mortality (adjusted relative risk 1.8, CI 1.10-2.82) [31]. In another study including 59 patients with IE due to S. aureus, the risk of embolization was greater in patients who had visible vegetations by both TTE and TEE compared with patients who had vegetations visualized only by TEE [28]. Another study noted that absence of valvular abnormalities on TTE may be associated with reduced incidence of complications [29]. (See "Role of echocardiography in infective endocarditis", section on 'Prognostic markers'.)

●Microbiology – The likelihood of symptomatic embolization is increased in the setting of IE due to fungal pathogens or S. aureus. In a review including 270 patients with fungal endocarditis, peripheral arterial embolization occurred in 45 percent of cases [33]. The most common sites were the cerebral circulation (17 percent) and femoral artery (16 percent). Another study including 384 patients with IE noted that emboli were more frequently observed in the setting of infection due to S. aureus and Streptococcus bovis infection [31].

●Presence of antiphospholipid antibodies – In one series including 91 patients with IE, the presence of antiphospholipid antibodies was associated with an increased risk of embolization (62 versus 23 percent); this may be due to increased endothelial cell activation, generation of thrombin, and defective fibrinolysis [30].

Effect of antibiotic therapy — The risk of embolization declines after institution of appropriate antimicrobial therapy, and serious embolic events after institution of therapy are rare after two weeks [19,34,35]. In one study including 1437 patients with left-sided IE receiving appropriate therapy, the incidence of stroke fell from 4.8 to 1.7 per 1000 patient-days between the first and second week of therapy [35]. The potential role of surgery to reduce the risk of embolization in patients with left-sided IE is discussed separately. (See "Surgery for left-sided native valve infective endocarditis", section on 'Vegetation characteristics and risk of embolization'.)

Metastatic abscess — Development of metastatic abscess occurs as a sequela of septic embolization; this may occur in the spleen, kidneys, brain, and/or soft tissues (such as the psoas muscle).

Patients with splenic abscess do not always have significant abdominal pain or splenomegaly on physical examination; in some cases, the only clue(s) may be persistent fever and/or recurrent bacteremia during or after completion of antimicrobial therapy [36]. Splenic abscess frequently requires splenectomy for cure. In one series including 27 patients with splenic abscesses, mortality among 17 patients who underwent splenectomy was 18 percent; mortality among 10 patients who did not undergo splenectomy was 100 percent [37]. (See "Splenomegaly and other splenic disorders in adults", section on 'Abscess and infarction'.)

Solitary or multiple brain abscess(es), including microabscess(es), can occur in IE; purulent meningitis can also be observed. The presence of meningitis due to S. aureus should suggest the possibility of concomitant S. aureus endocarditis. In one series including 33 patients with S. aureus meningitis, IE was diagnosed in 21 percent of cases [38]. Abscess drainage is required to control local infection and to prevent ongoing bacteremia. (See "Treatment and prognosis of bacterial brain abscess".)

Mycotic aneurysm — Mycotic aneurysm can develop in the cerebral or systemic circulation in the setting of IE, usually at points of vessel bifurcation. Although some authors use the term "mycotic" to describe infected aneurysm regardless of etiology, we limit the use of this term to those aneurysms that develop when material originating in the heart causes arterial wall infection and, subsequently, dilation [39]. (See "Overview of infected (mycotic) arterial aneurysm".)

Neurologic complications — Manifestations of neurologic complications include:

●Embolic stroke

●Brain abscess or cerebritis

●Purulent or aseptic meningitis

●Acute encephalopathy

●Meningoencephalitis

●Cerebral hemorrhage (due to stroke or a ruptured mycotic aneurysm)

●Seizures (secondary to abscess or embolic infarction)

Symptomatic cerebrovascular complications occur in up to 35 percent of patients [21,22,40-45]. Silent cerebrovascular complications (including ischemia and microhemorrhage) may occur in up to 80 percent of patients [21,46-48].

Neurologic complications may be the presenting symptom in patients with IE, and the possibility of IE should be considered in patients who present with stroke, meningitis, or brain abscess. In addition, unexplained fever accompanying a stroke in a patient with valvular disease can be an important clue for IE. In one retrospective review including nearly 18,000 patients with IE, stroke risk was significantly increased beginning four months before the diagnosis of IE and lasting five months afterward; the risk of stroke was highest in the month after diagnosis of IE (absolute risk increase of 9.1 percent [95% CI 8.6-9.5 percent]) [49]. In a cohort study including more than 5700 patients with left-sided endocarditis, the risk of hemorrhagic stroke was increased; it was generally attributable to mediating factors including presence of a mechanical valves, atrial fibrillation, and anticoagulation medication [50].

Among patients with IE, the incidence of cerebral emboli detected by magnetic resonance imaging (MRI) is markedly higher than the incidence of emboli detected based on clinical signs and symptoms [21,48,51]. In one study including 65 patients with IE, clinical findings consistent with embolism were observed in 20 percent of cases; among patients with no symptoms, emboli were detected on MRI in 46 percent of cases [51]. In another study including 60 patients with IE, clinical signs and symptoms of cerebral embolism were observed in 35 percent of cases; clinically silent emboli were detected on MRI in an additional 30 percent of patients [21].

In a study of 963 patients with IE, 7 percent had intracerebral hemorrhage [52]. Factors associated with intracerebral hemorrhage were low platelet count, severe valve regurgitation, ischemic stroke, systemic emboli, and the presence of a mycotic aneurysm.

Patient outcomes after a neurologic complication of IE are variable. In one study including 214 patients who underwent cardiac surgery for IE, 70 percent of patients with a preoperative stroke had full neurologic recovery; outcomes were worse in patients with stroke complicated by meningitis, abscess, or intracerebral hemorrhage [44]. Patient mortality in another series including 68 patients with stroke and IE was 50 percent at one year [53]. One study of 91 patients with S. aureus IE and neurologic manifestations noted mortality of 74 percent [42].

Renal complications — Renal complications of IE include renal infarction or abscess following septic embolization, glomerulonephritis (due to deposition of immunoglobulins and complement in the glomerular membrane), and drug-induced acute interstitial nephritis. Acute renal failure, defined as a serum creatinine of ≥2 mg/dL (177 mcmol/L), has been described in up to one-third of patients [54]. Immune complex-mediated renal disease, commonly associated with IE in the pre-antibiotic era, is now uncommon, especially in patients whose infection is detected and treated early. (See "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".)

Renal complications can also occur as a result of toxicity associated with administration of therapeutic drugs; this is particularly important in the setting of coadministration of vancomycin with aminoglycosides and among patients at the extremes of age. (See 'Complications related to therapy' below.)

Musculoskeletal complications — Musculoskeletal complications of IE include vertebral osteomyelitis and septic arthritis. Back pain in patients with IE should prompt consideration of vertebral osteomyelitis, particularly in the setting of S. aureus infection [55]. An initial imaging study performed early in the presentation of acute IE may be negative; worsening back pain should prompt repeat imaging. (See "Vertebral osteomyelitis and discitis in adults".)

Clues to the presence of septic arthritis in the setting of IE include involvement of multiple joints and involvement of the axial skeleton (eg, sacroiliac, pubic, or manubriosternal joints). Acute septic arthritis involving one or more joints may be the first clue to the presence of IE in a small percentage of patients, particularly for cases in which an organism with known propensity to cause IE (such as S. aureus, S. viridans, or non-group A beta-hemolytic streptococci) grows from a joint aspirate.

Pulmonary complications — Pulmonary complications occur most commonly in the setting of right-sided endocarditis. Embolization of a vegetation from the tricuspid or pulmonary valve can result in pulmonary infection. Clinical presentations may include bacterial pneumonia, lung abscess, pyothorax, pleural effusion, and/or pneumothorax. Pulmonary complications have been associated with longer length of hospital stay, higher hospital costs, and increased hospital mortality [56].

Complications related to therapy — Patients with infective endocarditis can develop a number of the complications associated with prolonged parenteral antimicrobial therapy or surgery:

●Aminoglycoside-induced ototoxicity or nephrotoxicity, particularly in patients who receive simultaneous treatment with vancomycin and aminoglycosides (see "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity")

●Postoperative mediastinitis or early postoperative prosthetic valve endocarditis (see "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology")

●Mediastinitis or early postoperative prosthetic valve endocarditis (see "Postoperative mediastinitis after cardiac surgery")

●Intravenous catheter-associated thrombosis (see "Catheter-related upper extremity venous thrombosis in adults")

●Drug fever (see "Drug fever")

●Allergic or idiosyncratic reactions to various antimicrobial agents – Some agents (such as beta-lactams) that are generally tolerable for short courses may be associated with significant reactions (acute interstitial nephritis) in the setting of long-term therapy

●Bleeding due to disturbances in coagulation caused by anticoagulants (eg, in prosthetic valve endocarditis) (see "Antithrombotic therapy in patients with infective endocarditis")

OUTCOME — In the United States between 1980 and 2014, the mortality rate for endocarditis was 2.4 per 100,000 [57]. Among patients with infective endocarditis (IE), in-hospital mortality rate is 18 to 23 percent; the six-month mortality rate is 22 to 27 percent [58-62]. The outcomes in patients with neurologic complications are described above (see 'Neurologic complications' above). In a case series of 202 patients with IE in people who inject drugs, the all-cause mortality rate was 33.7 percent with lower mortality rates in those who had surgery or had referral for addiction therapy [63].

Some data suggest that the following characteristics appear to confer increased risk of mortality in patients with infective endocarditis:

●Microbiology (mortality is higher in the setting of S. aureus infection than streptococcal infection) [59,61,64]

●Heart failure [60,62]

●Diabetes mellitus [59]

●Embolization [59,64]

●Perivalvular abscess [8,10,62]

●Larger vegetation size [31,64]

●Female sex [31]

●Low serum albumin [58]

●Persistent bacteremia [62]

●Abnormal mental status [61]

●Poor surgical candidacy [61]

●Positive valve culture [65]

Echocardiographic findings may be useful predictors of outcome. One propensity-matched subset analysis including more than 700 patients with S. aureus left-sided native valve IE noted that intracardiac abscess and left ventricular ejection fraction <40 percent were independent predictors of in-hospital mortality, and intracardiac abscess and valve perforation were independent predictors of one-year mortality [66].

The association between cardiac surgery, heart failure, and mortality risk is uncertain. In one prospective report, neither cardiac surgery nor heart failure was independently associated with in-hospital mortality [59]. However, among patients with moderate to severe heart failure, other studies have noted an association between cardiac surgery and lower mortality rate compared with medical therapy alone. In one study including approximately 260 patients, the presence of three risk factors (heart failure, periannular complications, and S. aureus infection) during the first 72 hours of hospitalization was predictive of need for urgent surgery or in-hospital mortality [67]. Subsequent prospective validation of the model noted that one risk factor conferred approximately 60 percent risk of adverse outcome; three risk factors conferred nearly 100 percent risk of adverse outcome.

Issues related to the association between cardiac surgery and clinical outcome are discussed further separately. (See "Surgery for left-sided native valve infective endocarditis".)

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

●Complications of infective endocarditis (IE) include cardiac, neurologic, renal, musculoskeletal, and pulmonary complications as well as complications related to systemic infection (including embolization, metastatic infection, and mycotic aneurysm). More than one complication can occur simultaneously. (See 'Complications of endocarditis' above.)

●Cardiac complications include heart failure, perivalvular abscess, pericarditis, and intracardiac fistula. Heart failure is the most common indication for cardiac surgery in patients with IE and is the most common cause of death. (See 'Cardiac complications' above.)

●Forms of metastatic infection include septic embolization, metastatic abscess, and mycotic aneurysm. Septic emboli can occlude or damage virtually any vessel in the systemic or pulmonary arterial circulation. Metastatic abscess can develop as a sequela of septic embolization; this may occur in the spleen, kidneys, brain, soft tissues, and/or lungs. Mycotic aneurysm can develop in the cerebral or systemic circulation in the setting of IE, usually at points of vessel bifurcation. (See 'Metastatic infection' above.)

●Neurologic complications include stroke, brain abscess, meningitis, and other manifestations; these can be the presenting symptom in patients with IE. (See 'Neurologic complications' above.)

●Renal complications of IE include renal infarction or abscess following septic embolization, glomerulonephritis (due to deposition of immunoglobulins and complement in the glomerular membrane), and drug-induced acute interstitial nephritis. (See 'Renal complications' above.)

●Musculoskeletal complications of IE include vertebral osteomyelitis and septic arthritis. Back pain in patients with IE should prompt consideration of vertebral osteomyelitis, particularly in the setting of S. aureus infection. Clues to the presence of septic arthritis in the setting of IE include involvement of multiple joints and involvement of the axial skeleton (eg, sacroiliac, pubic, or manubriosternal joints). (See 'Musculoskeletal complications' above.)

●The six-month mortality rate among patients with IE ranges up to 27 percent. A number of factors appear to confer increased risk of mortality, including microbiology, heart failure, embolization, and candidacy for cardiac surgery. (See 'Outcome' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Sexton, MD, who contributed to earlier versions of this topic review.