Infective Endocarditis

Infective Endocarditis (IE) is an infection of the endocardium of the heart. The autopsy findings were first described in 1723 and in 1885 William Osler described the first comprehensive account of endocarditis. IE produces both intracardiac effects (e.g. valvular insufficiency) and a wide variety of systemic effects; both from emboli (sterile and infected) and a variety of immunological mechanisms.

It is a disease that is easily overlooked or misdiagnosed and clinicians should be vigilant and well versed in the manifestations of IE to avoid missing the diagnosis. This account puts emphasis on clinical factors helpful in diagnosis. The disease has evolved over the years in tandem with changes in the prevalence of associated diseases and treatments for cardiac disease. There is often not a clear distinction between the typical acute IE (rapidly progressive, normal valves) and the subacute IE (abnormal valves, progressing over months), but the classification still has clinical value.

• The incidence of IE is approximately 2-4 cases per 100,000 per year.
• Incidence has remained constant for 50 years despite changes in the factors affecting incidence (previously rheumatic valve disease and congenital cyanotic heart disease accounted for most cases):²
  • Proliferation of invasive vascular procedures.
  • Increase in recreational drug abuse.
  • Decline in rheumatic heart disease (less than 20% of cases of IE).
  • In the elderly 50% of patients have calcific aortic stenosis underlying their IE.
  • Congenital heart disease accounts for 15% of cases (bicuspid aortic valve being the most common).
  • Previous IE with valvular damage is the most significant risk factor.
  • 75% of IE in intravenous drug abuse has no underlying valvular abnormality.
  • Prosthetic valve implants are used more often and account for 10-20% of cases of IE.
  • Antibiotic prophylaxis has probably had little effect on decreasing the incidence of IE.
• Figures for incidence are similar between countries.
• It is 3 times more common in men.
• It is increasing in elderly patients (25-50% of cases occur in the over 60s) often associated with other disease (diabetes, cancer, alcoholism).

It is important to understand the pathophysiology to understand the aetiology, clinical presentation, complications and management.
All cases share:

• Bacteraemia: spontaneous or nosocomial
  • Spontaneous:
    • Gingival disease most common and usually streptococcal
    • Activities of daily living causing transient bacteraemia (brushing teeth, opening bowels)
    • Occasionally infections such as pneumonia and pyelonephritis
  • Nosocomial (all with rates as high as 20%, even higher for dental extractions):
    • Endoscopy/colonoscopy - E. coli, bacteroides, streptococci, diphtheroids
    • Barium enema- enterococci, aerobic and anaerobic Gram negative organisms
    • Dental extractions - S viridans
    • Transurethral resection of prostate - coliforms, enterococci, S. aureus
    • Intravascular lines especially central venous lines- increasing incidence-S. aureus
• Adherence of the organisms:
  • Complex process
  • Once established on surface aggregation of platelets and fibrin deposition occurs
  • Bacteria multiply
  • Layers of platelet and thrombin form protecting from neutrophils, host defences and antibiotics
• Invasion of the valvular leaflets:
  • Complex process
  • Proliferation of fibroblasts and capillaries
  • Mixed patches of healing and destruction of tissue
  • Healing falls behind
  • Valvular insufficiency from perforation of cusps and rupture of chordae tendineae (with subacute IE)

All cases share a nonbacterial thrombotic endocarditis (a sterile fibrin-platelet vegetation) as the prerequisite for adhesion and invasion. The site of this thrombus is influenced by the Venturi effect, with deposition of thrombus on the low pressure side. For example, beyond a narrowing or stenosis (and on the atrial side of a leaking mitral valve, but the ventricular side in atrial insufficiency). There are differences in the different clinical situations:

• Acute IE. The thrombus may be produced either by the invading organism or by valvular trauma (pacing wires, catheters etc.).
• Subacute IE. Sufficient innoculum of bacteria required to allow invasion of the thrombus, bacteria clumping with production of agglutinating antibodies.
• Nonbacterial thrombotic endocarditis can result from, for example, renal failure, neoplasia, systemic lupus erythematosus or malnutrition.

• Mitral valve
• Aortic valve
• Combined mitral and aortic valve
• Tricuspid valve
• Pulmonary valve-rare

Note: Mechanical and bioprosthetic valves are affected equally.

Pathophysiology of complications

The complications for both acute and subacute IE are:

• Congestive cardiac failure:
  • This is the most frequent complication for both
  • Aortic valve insufficiency is the most common intracardiac complication of subacute IE.
  • It can occur a year after microbiological cure.
• Arterial embolisation:
  • The prevalence is similar for both acute and subacute IE.
  • The incidence of emboli has fallen in the antibiotic era.
  • However emboli are usually sterile because causative organisms are minimally invasive.
  • Markedly increased levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins occur.
  • These circulating immune complexes cause extracardiac complications:
    • Glomerulonephritis
    • Peripheral manifestations (Osler nodes, Roth spots, subungual haemorrhages)
    • Musculoskeletal abnormalities.
    • Emboli occur most commonly in coronary arteries, kidneys, brain and spleen (cerebral emboli occur in about a third of patients).
    • Vegetations of S. aureus, H. influenzae, H. parainfluenzae and the fungi are more likely to embolise than those of S. viridans.
    • Vegetations of mitral valve most likely to embolise.
    • Infarction at the site of embolisation is common but abscess formation is not.
    • Neurological embolic damage (cranial nerve palsies, cerebritis).
  • Mycotic aneurysms can occur (for example in abdominal aorta, pulmonary, splenic and coronary arteries).

Acute bacterial endocarditis differs microscopically from subacute disease. Differences include:

• Vegetations develop rapidly and contain no fibroblasts
• Little evidence of repair
• Vegetations contain polymorphonuclear leucocytes and organisms
• Necrosis occurs within the expanding vegetation
• Rupture of leaflets, papillary muscles and chordae tendineae rapidly occurs
• Complications result from intracardiac disease:
  • Valvular insufficiency
  • Fistulas (for example aortocardiac)
  • Aneurysms of the sinus of Valsalva
  • Myocardial abscesses
  • Mycotic aneurysms
  • Pericarditis
  • Septic emboli to coronary arteries
  • Intraventricular abscesses
  Metastatic infection (suppurative emboli):
  Multiple abscesses can occur anywhere (kidney, brain, heart)
  • Mycotic aneurysms, although paradoxically less often than in subacute IE
• Immunological phenomena not associated with acute disease

History

Subacute IE

• Early disease subtle and nonspecific
• Indolent process which may include:
  • Fatigue
  • Low grade fever
  • Flu-like illness
  • Polymyalgia like symptoms
  • Loss of appetite
  • Back pain
  • Pleuritic pain
  • Abdominal symptoms (may be pain, vomiting and appendicitis like symptoms)
  • Symptoms akin to rheumatic fever
  • Weight loss
• Cerebrovascular accident- less common
• Congestive cardiac failure- less common
• May be history of:
  • Invasive procedures (see above)
  • Recreational drug use
  • Dental disease
  • Gingivitis- most cases caused by transient bacteraemia from this
  • Symptoms usually arise 2 weeks after invasive procedures but diagnosed after 6 weeks
  • Fewer than half patients have previously diagnosed valvular disease
• Developing disease produces myriad of further clinical features of embolic or immunological origin when treatment/ diagnosis delayed for weeks/ months:
  • Acute meningitis- signs and symptoms but with sterile CSF
  • Hemiplegia from emboli in the middle cerebral artery (50% of patients may be first manifestation, has high mortality)
  • Renal infarcts causing painless haematuria
  • Splenic infarction causing pain
  • Blindness from retinal artery occlusion
  • Myocardial infarction from emboli in the coronary artery
  • Pulmonary emboli
  • Interstitial nephritis or proliferative glomerulonephritis from deposition of circulating immune complexes
  • Renal failure may result
  • Musculoskeletal symptoms (nearly half of patients) often from immunologically mediated synovitis
  • Immune-mediated vasculitis (causing Osler nodes and Roth spots)
  • Palpitations from immune-mediated myocarditis
  • Back pain (15% of patients) may have origin in immune complex deposition in disc spaces

Acute IE

• Rapidly progressive, aggressive illness
• Acute high fevers
• Rapid onset congestive cardiac failure from valve destruction
• Complications develop rapidly (within 1 week)
• Wide spectrum of neuropsychiatric complications of CNS involvement
• May be history of drug abuse
• May be history as above of invasive procedures

IE related to intravenous drug abuse

• Some studies report as many as half of all cases of IE are related to intravenous drug abuse
• A common association with 5-8% of intravenous drug abusers who are febrile having IE
• Frequently presents with pneumonia and empyema
• Often presents with manifestations of metastatic infection
• P. aeruginosa infections often associated with neurological involvement
• In 75% of such cases the underlying valves are normal

Prosthetic valve endocarditis

• Accounts for 10-20% of cases of IE
• This is infection occurring within 60 days of valve implantation (or 12 months for coagulase- negative staphylococci)
• Similar clinical features to native valve endocarditis
• Complications such as CCF and embolic stroke occur earlier
• CCF is more severe

Pacemaker related IE

• It is more common to get infections elsewhere with pacemaker implantation (the generator pocket being the most common site)
• IE is an uncommon association (0.5% of implanted pacemakers)

Nosocomial IE

• Often presents with sepsis syndrome (fever, hypotension, multiple organ failure)
• Patients often on ITU
• About half of such patients have prosthetic valves

Examination

IE can present in a myriad of different ways. The differential diagnosis could include all those conditions which occur as a complication or with progression of the disease. Some of the more unusual diseases which may also have similar complex and varied manifestations are:

• Systemic Lupus Erythematosus
• Atrial Myxoma and other cardiac neoplasms
• Lyme Disease
• Antiphospholipid Syndrome
• Polymyalgia Rheumatica
• Reactive arthritis

Basic investigations should be performed (full blood count, ESR, CRP, biochemistry, ECG) but the most discriminating investigations are elaborated on below.

• Laboratory investigations
  • Blood cultures These are key to making the diagnosis. Note:
    • Blood cultures are used to demonstrate bacteraemia of 30 minutes or more duration
    • Draw 3 to 5 sets of blood cultures over 24 hours
    • In acute IE 3 sets drawn from different venepuncture sites over 30 minutes demonstrates continuous bacteraemia
    • If cultures negative 24 hours after stopping antibiotics repeat after 7 days and if still negative reconsider IE diagnosis
    • Blood should not be drawn from IV lines (unless diagnosing line infection when simultaneous line and peripheral vein sampling may be used)
    • Prior use of antibiotics commonly gives false negative results
    • Probably 50% of culture results are estimated to be falsely positive
    • Fastidious organisms may require special culture media or prolonged incubation
    • HACEK organisms may require 3 weeks of culture and brucella organisms up to 6 weeks
  • Serological tests. These may be necessary to detect some organisms (for example legionella, chlamydia, brucella and coxiella species).
• Imaging studies
  • Blood cultures are very important to diagnosis but specific and sensitive indirect diagnostic techniques are increasingly important
  • Indirect techniques are more important because:
    • The nature of valvular infections has changed
    • Fastidious organism infection is increasingly recognised
    • Classical peripheral stigmata of the disease occur less often
    • Elderly chronically ill or immunosuppressed patients present less often with fever and classical stigmata
  • Echocardiography is the indirect investigative method of choice. Note in general terms that:
    • Echocardiography particularly useful in the elderly
    • Echocardiography especially of use when clinical picture of IE but negative cultures
    • Echocardiography useful to predict complications such as embolisation:
      • Larger vegetations (>10mm diameter)
      • Multiple vegetations
      • Pedunculated vegetations
      • Prolapsing vegetations
    • Diagnosis of IE can never be excluded with negative echocardiogram (of whatever type)
    • Echocardiography should not be used to screen for IE because of high (15% plus) false positive rate (caused by thickened valves etc)
    • Transthoracic echocardiography (TTE):
      • Can detect vegetations in 60% of native valve endocarditis but much less often in prosthetic valves
      • TTE is good enough for most cases of IE
    • Transoesophageal echocardiography (TEE):
      • Was developed to visualise prosthetic valves and right sided pathology
      • It detects over 90% of all vegetations
      • TEE is better at detecting myocardial abscesses and vegetations on pacemaker leads
  • Two dimensional cardiac ultrasound Doppler studies have been a helpful advance providing more information on vegetations:
    • This may help in diagnosis but also in predicting risk of embolisation
    • Useful for visualising jet lesions and cusp perforation
  • Radionucleotide studies are of little value except for detecting splenic abscesses which are refractory to antibiotic treatment.
• Electrocardiogram. 10% of patients with IE will develop conduction defects.
• Cardiac catheter studies. Rarely required to diagnose IE or complications.

Diagnostic criteria^1,5

Criteria which incorporate clinical, echocardiographic, microbiological and pathological criteria have been developed and can increase the number of definite diagnoses of IE.⁵ They can overdiagnose IE and may be less useful in subacute IE. The so called Duke criteria are considered superior to older similar criteria.^6,7 These incorporate:

• Major blood culture criteria:
  • 2 positive blood cultures for typical IE organisms
  • Persistently positive cultures for such organisms drawn >12 hours apart
  • 3 or more positive cultures drawn at least 1 hour apart
• Major echocardiographic criteria:
  • Positive result and no alternative explanation
  • Myocardial abscess
  • Partial dehiscence of prosthetic valve
  • New valvular regurgitation
• Minor criteria:
  • Predisposing cardiac condition
  • Intravenous drug use
  • Fever (38 degrees C or over)
  • Vascular lesions
  • Immunological phenomenon
  • Positive cultures less than 'major'
  • Positive echocardiographic results but insufficient for major criteria
• Definitive pathological diagnosis from tissue
• Definitive clinical diagnosis:
  • 2 major
  • 1 major and 3 minor
  • 5 minor criteria
• Rejection criteria include:
  • Presence of firm alternative diagnosis
  • Resolution of manifestations of IE in under 4 days
  • No pathological evidence after autopsy or surgery with 4 or fewer days of antibiotics

These are an inherent part of the progression of the disease. Patients should be monitored for:

• Valve dysfunction
• Myocardial abscesses
• Embolic phenomena
• Heart failure
• Metastatic infection
• Immunological disease and organ dysfunction
• Complications even after bacteriological cure
• Conduction defects (patients with IE should have daily ECGs)

See Management of Infective Endocarditis.

This varies markedly according to a variety of factors. The following outlines the range of prognosis when managed appropriately:

• Native valve endocarditis:
  • S. viridans 98% cure rate
  • S. aureus 60-90% cure rate with worse results in occurring in those NOT abusing intravenous drugs
  • Fungal infections- cure rate less than 50%
• Prosthetic valve endocarditis:
  • Cure rates at least 10% lower than above for each variety
  • Surgery needed more often

See Prevention of Endocarditis.
It should be borne in mind that around 25% of cases of IE occur as a result of invasive procedures but that only about half of patients developing IE were identified as at risk and requiring antibiotic prophylaxis. It is therefore only possible to prevent about 10% of cases with prophylactic antibiotics.