Endocarditis

Context and definition

Endocarditis is defined as damage to the endocardium associated with thrombus formation. The endothelial lining of the heart covers all internal structures of the heart including valvular surfaces. Endocarditis can be infective if colonised by bacteria or fungi, or non-infective.

Infective endocarditis has a relatively low prevalence in developed countries, with incidence between 2-6 cases per 100,000 population per year. This incidence rises 30 to 200 fold in populations of intravenous drug users. Left untreated it is a devastating disease that can prove fatal within a matter of weeks. Early detection and treatment is therefore paramount to improve clinical outcome.

Availability and use of effective antibiotics has altered both the patient profile and disease progress. The usual patient now presents in the 6th decade of life, compared to the pre antibiotic era when the typical patient was in their 30s. Moreover, use of antibiotics has altered the progress of the disease, and the previous classification of endocarditis into acute, sub-acute and chronic is no longer in widespread use.

Vegetations on valves does not always represent an infective process. Loefflers endocarditis is a part of the hypereosinophilic syndrome, and responds well to treatment with steroids, hydroxyurea and anticoagulation. Non Bacterial Thrombotic Endocarditis (NBTE) is associated with endocardial damage due to trauma, or with hypercoagulable states, and though it is usually sterile it is a site for subsequent infection.

Even though the emergency physician may not be involved in the long-term management of endocarditis, they play a crucial role in diagnosis and initial management of endocarditis and its complications.

Aetiology

Endocardium is non sticky and normally resists bacterial seeding. Most cases of infective endocarditis relate to structural defects like congenital malformations, Rheumatic heart disease, calcific degenerative valvular change, prosthetic heart valves and Mitral valve prolapse (see figure 1). Other risk factors include injectable drug use, pacemaker insertion and previous endocarditis (the latter leading to structural defects in the endocardium making it prone to bacterial adherence).

Figure 1: Cardiac Conditions predisposing to Endocarditis, NICE CG641

Pathophysiology

The hallmark of endocarditis is formation of vegetations that bind to valves or mural endocardium. Aberrant flow predisposes to a collection of fibrin, platelets and scant inflammatory cells.

Figure 2: Aortic Valve Vegetation

Microorganisms that enter blood stream from skin, mucosa or other sites of focal infection bind to the vegetation and cause local infection leading to a pro-coagulant state. Further fibrin deposition, platelet aggregation and bacterial invasion lead to an infection cascade causing infective endocarditis. Staphylococcus aureus possesses fibronectin binding proteins and is capable of binding to intact endothelium and therefore can infect previously uninfected endocardium.

Figure 3: Excised Aortic Valve with vegetation, note disfigurement of valve

Bacterial micro colonies deep within the vegetation are dormant and therefore difficult to eradicate. Superficial bacterial colonies tend to embolise distally causing septic phenomenon as well as reinfection of vegetation. A constant infection leads to the three hallmarks of the disease:

1. constitutional symptoms which are cytokine mediated
2. local spread of infection causing destruction of myocardium
3. distal blood borne septic embolisation

Constant shedding of bacteria is detected in blood cultures. In laboratories using modern techniques positive culture rates are in excess of 90%, reaching 98% in people without previous antibiotic exposure.

Traditionally Streptococcus has been considered the primary pathogen responsible, however Staphylococcus is implicated in slightly more native valve disease, and is overwhelmingly the main pathogen in nosocomial infections and those in injectable drug users (Table 1)

Recurrence is a common theme, as damaged valves are prone to further infections; 20% of patients with endocarditis have had previous infection with this rate going up to 40% in those who inject drugs. This is by far the commonest risk factor.

Cardiac Manifestations: Cardiac failure can complicate the disease in nearly a third of the patients. This is usually due to involvement of the aortic valve, but can be due to intra-cardiac fistulae formation, abscesses or conduction defects caused as a direct result of local bacterial infection of the myocardium. Although coronary artery embolisation can lead to acute ischaemia, this is rare.

Non cardiac Manifestations: Almost half the patients will have distal seeding of septic emboli causing non cardiac manifestation. This is most apparent in skin, meninges, spleen, eyes and kidneys and cause significant symptoms. Infection of blood vessels leads to mycotic aneurysms that are prone to rupture. 40% of patients will develop neurological symptoms during the course of their illness; these are usually related to micro abscesses and rarely require surgical intervention.

Immune complex deposition can result in glomerulonephritis and renal dysfunction.

During the illness there can be constant shedding of emboli. Vegetations > 10mm in size and mitral valve vegetations are more prone to embolise.

Adequate treatment reduces rate of embolisation by 10 fold, and causes prompt resolution of systemic constitutional symptoms and rapid improvement of renal dysfunction. However, continued embolisation is not a marker of treatment failure as this can persist despite adequate bacterial clearance.

Table 1: Bacteria Isolated in Endocarditis (%)2

HACEK: Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella

Learning Bite

Endocarditis usually occurs on previously damaged endocardium, and incidence greatly increases in injecting drug abusers.

The classic triad of fever, new murmur and microcytic anaemia is rarely seen as these symptoms develop over time and are therefore not found together at the same time. Early detection and intervention changes the course of the disease significantly and reliance should not be made on classical features for diagnosis.

Symptoms and signs span the continuum between the indolent presentations of sub-acute infection to the catastrophic presentation of acute endocarditis. Fever is present in nearly 90% of cases and is the most consistent feature of the disease (see Table 2). Cardiac murmurs will be detected in nearly the same proportion but only one third of patients may have these at initial presentation. Of note is that cardiac murmurs may be very difficult to appreciate in right-sided disease, such as is prevalent in injectable drug use, due to their soft nature and absence of quiet examining areas in most emergency departments (ED).

Table 2: Incidence of Clinical Features in Infective Endocarditis2

The acuity of the presentation may be related to the offending bacterium. Beta haemolytic Streptococcus and Staphylococcus usually cause acute infections whereas HACEK (HACEK: Haemophilus, Actinobaccilus, Cardiobacterium, Eikenella, Kingella) group is usually associated with an indolent process.

Learning Bite

Fever is the commonest clinical manifestation

Pitfall

Right-sided cardiac murmurs are often soft and can be easily missed in the emergency department.

History

A detailed history should focus on eliciting risk factors for Infective Endocarditis so as to highlight the at risk population groups. (See Figure 1)

Further enquiry should be made to elicit cardinal features of the disease especially fever, chills, arthralgia and constitutional symptoms like loss of appetite and malaise. (Table 2)

It is also important to elicit history suggestive of complications: sudden shortness of breath, stroke like symptoms and visual disturbance should lead to investigation and further work up.

Examination findings

Apart from a detailed examination of skin and mucosae, careful auscultation in a quiet environment may help distinguish soft right sided murmurs. Any signs of cardiac failure must be noted.

The abdominal exam may reveal splenomegaly.

A brief neurological examination should be done to ensure absence of cerebral and cerebellar stroke.

General examination may reveal some classical peripheral manifestations of Infective Endocarditis.

Four clinical manifestations are linked to IE, and though these are getting rare due to rapid treatment, they may present vital clues in situations where diagnosis is unclear.

Roth spots: These are described as canoe-shaped linear haemorrhagic spots with a light central area. Their aetiology is unclear, but is thought to be related to anoxia leading to increase in venous pressure and rupture.

Figure 4: Roth spots

Oslers nodes: These are painful, erythematous nodules on pads of fingers and toes. They may have a dual aetiology as they are related to both: septic micro-emboli and immune complex related vasculitis. These usually develop late in the illness and may be seen in other conditions like typhoid and gonococcemia. They appear rapidly and resolve without sequelae with treatment.

Figure 5: Oslers Nodes

Janeway Lesions: These are haemorrhagic nodular lesions with an irregular border present on palms and soles. They are related to micro-abscess formation and localised necrosis. Unlike Oslers nodes, these present early in the disease and are non-tender in nature.

Figure 6: Janeway Lesions

Splinter Haemorrhages: These are linear minute capillary engorgements usually in distal third of the nail bed. They are usually painless, and though reddish brown to start with turn dark brown or black in a few days. They may be related to other conditions like Psoriasis, meningococcemia or even present in healthy individuals.

Figure 7: Splinter Haemorrhages

Learning Bite

Careful examination of skin, mucosae and fundus is important to pick up peripheral manifestations of Endocarditis.

Pitfall

None of the peripheral signs are pathognomic for Endocarditis – careful clinical correlation must be made.

Duke Criteria for diagnosis³

Diagnosis of Endocarditis is based on blood cultures and echocardiographic findings. Duke criteria are frequently used to confirm or rule out endocarditis and involve use of laboratory and echocardiographic evidence. Two major, or one major and three minor, or five minor criteria can confirm endocarditis. (See Figure 7)

Learning Bite

Blood cultures and echocardiography are bedrocks of diagnosis.

Blood cultures

Positive blood cultures remain the most important laboratory test for confirming endocarditis. Blood cultures are positive in up to 98% of patients who have not been previously treated with antibiotics. With modern systems HACEK (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella and Kingella) organisms can be successfully cultured, reducing rate of culture negative endocarditis to about 5-10%.

At least two sets of blood cultures should be taken from different venepuncture sites on presentation, and ideally repeated one hour later. Further blood cultures should be taken after 12 hours and then regularly to monitor clearance.

Blood and urine tests

Haematological and serological tests contribute to making the diagnosis and marking progress of the disease and urinalysis is a useful initial screen to evaluate renal involvement. (See Table 3)

Echocardiography

Echocardiography is a critical investigation in both diagnosis of infective endocarditis and evaluation of complications. It is used to detect vegetation and look for intra-cardiac manifestation of disease.

Figure 8: Vegetation on Tricuspid Valve

Transthoracic echocardiography (TTE) has a sensitivity of about 65% but is unable to pick up vegetation smaller than 2 mm and is hampered by technical issues like body habitus and emphysema. It is a very specific test detecting vegetation in > 90% of patients with endocarditis7. Due to low sensitivity TTE should not be used for screening unless there is low pre-test probability of Endocarditis. TTE is inadequate for evaluation of prosthetic valves, localised abscess formation and vegetation less than 2mm in size.

Trans-oesophageal echocardiography (TOE) has a sensitivity of 90% and is much better at detecting cardiac structural abnormalities7. It is therefore the investigation of choice in patients with a high pre-test probability of Endocarditis as well as in patients with known structural heart disease, prosthetic valves or an unsuitable body habitus. A negative scan does not completely rule out infective endocarditis, especially early in the disease and, where index of suspicion is high, this is an indication for a repeat examination.

Learning Bite

TOE has a higher sensitivity than TTE and is the investigation of choice.

An initially negative TOE does not completely exclude the diagnosis and where the index of suspicion is high it should be repeated after an interval.

Other investigations

1. Cardiac catheterisation is useful for pre surgical evaluation but is not recommended routinely.
2. Electrocardiogram and chest X-ray will be required to refine the diagnosis, exclude other causes for the clinical presentation and evaluate potential complications (eg cardiac failure and ischaemia).
3. Ultrasound and CT / MRI scans may be required to detect peripheral manifestation due to embolisation. This may include imaging the CNS to look for cerebral abscess or ischaemic stroke. Continued fever and positive blood cultures despite adequate treatment should prompt visualisation of abdominal viscera for detection of abscess, especially in the spleen.

Special case: Injectable drug users

Injectable drug use increases rate of infection as much as 200 fold. This population presents a specific risk and should be evaluated with special care in the ED.

The majority of cases involve the right side of the heart, with the tricuspid valve being particularly prone. A tricuspid murmur is difficult to appreciate due to its soft nature and lack of quiet consultation rooms in a busy emergency department.

Staphylococcus is the main organism involved in right sided infections and incidence of MRSA is significant.

Due to repeated exposure, there is high recurrence in this group nearing 40%. Recurrent infections are likely to involve the left side and may have varied organisms including Pseudomonas, Bacillus, Lactobacillus, Corynebacterium and Candida. Occasionally poly-microbial disease is identified.

Learning Bite

Injectable drug users are prone to repeated infections.

Emergency management

The focus of management in the Emergency Department should be on suspecting and diagnosing Endocarditis. Patients sometimes present with catastrophic illness relating to acute cardiac failure, severe sepsis, cerebral abscess and stroke or prosthetic valve failure.

Acute treatment for these complications should lead to prompt resuscitation following a structured ABC approach. Investigations and treatment should be based on the particular complication. Acute cardiac failure may require diuresis and supported ventilation. Sepsis should be treated in line with principles of Early Goal Directed Therapy. Some complications, like dehiscence of prosthetic valve, may require urgent surgery as a lifesaving procedure and this should be considered. The indications for surgery are discussed later in a separate section.

Antibiotics

Empirical antibiotics should be started after initial blood cultures are drawn based on the common pathogens suspected for the particular patient group.

It is difficult to eradicate bacteria as they reside in avascular areas, thereby escaping host defences. They may be dormant and relatively inactive if located deep within vegetation, and patients are prone to repeat infections from subsequent embolisation and re-seeding. Keeping this in mind high concentrations of bactericidal antibiotics are needed for prolonged periods to attempt ultimate eradication. Usual regimes are tailored to cultures and last 4-6 weeks for native valves and 6-8 weeks for prosthetic ones. It is very important that antibiotics are tailored to cultures and sensitivities of bacteria in order for treatment to be effective and therefore consultation with local microbiology team is essential.

Penicillin or Cephalosporins are usual first line antibiotics, with Vancomycin for cases of MRSA (Methicillin ResistantStaphylococcus aureus) or Penicillin allergy. Good laboratory support with precise MIC (Minimum Inhibitory Concentration) estimation can help tailor dosage of Penicillin so that adequate serum concentrations can be achieved. Gentamicin is frequently used in the acute phase for its synergistic interaction with Penicillin. Regular discussion with microbiologists should aid appropriate treatment planning.

Once antibiotic therapy is commenced, regular blood cultures should be taken, as they become negative with effective therapy. Temperature usually settles in 6-7 days, quicker with Penicillin than Vancomycin. Persistence of temperature beyond 7 days should lead to re-evaluation of the patient: repeat echocardiography to rule out abscess formation, and appropriate evaluation of extra cardiac structures to look for abscess and embolic phenomena. Ceftriaxone is widely used for its convenience (less frequent dosage requirement) and wide cover of most organisms including the HACEK group.

Fever with sterile blood cultures could result from drug associated fever or reaction and this should be kept in mind. Effective treatment reduces incidence of embolic phenomenon from 13 per 1000 patient days in the first week of treatment to 1.2 per 1000 patient days in the third week of treatment4. Therefore, persistence of fever or occasional embolic phenomena are not, of themselves, necessarily an indication of treatment failure.

The size of valvular vegetation is not correlated with cure and is a poor indicator of effectiveness of treatment. Though most vegetation reduces in size with effective therapy, some remain unchanged, and 25% actually increase in size at 3 months.

Learning Bite

• Prolonged intravenous antibiotic use to maintain a high MIC is essential to ensure cure.
• Patients can present to the Emergency Department with life threatening complications.

Role of surgery (see table 4)

Surgery may be required for urgent treatment of both intra-cardiac and neurological complications. There are no absolute indications for surgery though, and its use must be evaluated after careful analysis of risks and benefits. It is important for the emergency physician to be able to recognise when urgent surgery may be required to treat a complication of endocarditis.

(i) Cardiac indications for surgery:

The usual indication for surgery is congestive cardiac failure associated with acute valvular dysfunction. This is usually caused by valve dehiscence or perforation and is most apparent in the aortic valve. Acute valve failure carries a high mortality, 60-90% at 6 month. Surgery in this situation dramatically improves survival reducing mortality to 20-40% for native valve disease and 35-55% for prosthetic valve disease.5 Surgery may also be required to relieve stenosis as a result of vegetation.

Surgery should also be considered for perivalvular infections and abscesses (see figure), uncontrolled infection, removal of large vegetation like in fungal infection, and for Staph aureus associated prosthetic valve disease. Peri-valvular disease should be suspected in patients with persistent and unexplained fever despite appropriate therapy. It complicates 45-50 % of prosthetic valve infections, but also occurs in 10-15% of native valve infections. Surgery is particularly beneficial if medical therapy is not successful, where there is local spread or valve dehiscence.

Staph aureus endocarditis, particularly in prosthetic valve disease derives significant benefit from surgical debridement. Mortality is reduced from 70% for medical management to nearly 25% with appropriate surgery.

Figure 8: Peri-valvular abscess (Aortic valve has been removed)

Learning Bite

Expeditious surgery decreases mortality in prosthetic valve disease and acute valvular failure.

(ii) Extra-cardiac indications for surgery:

In cases of persistent embolisation surgery may be considered particularly if it can achieve other goals like valve repair or abscess drainage. If there is an indication for surgery, it should not be delayed as this only increases risk of further embolisation and complications. However if patients have had neurological complications surgery must be delayed for 2-3 weeks after a non-haemorrhagic stroke and 4 weeks after a haemorrhagic one as surgery increases risk for further sequelae.

Splenic abscesses may require guided percutaneous drainage or splenectomy.

Persistent mycotic aneurysms, especially when they involve cerebral vessels may also require surgical intervention.

Antibiotic Prophylaxis

Traditionally prophylaxis has been offered to all people undergoing invasive procedures, both dental and non-dental, who have pre-existing endocardial defects.

NICE (National Institute of Clinical Excellence), after a thorough review, found no evidence to support this practice and recommends that routine antibiotic prophylaxis is not used.1

The current recommendation is to use prophylaxis only in cases where there is a procedure involving an area with active infection, and to promptly treat infections in patients who are at risk of developing infective endocarditis.

A quick reference guide is found on: http://www.nice.org.uk/nicemedia/live/11938/40014/40014.pdf

Figure 9: NICE guideline on prophylaxis for Endocarditis, CG64

Figure 10: Guidance on appropriate use of Antibiotics, NICE CG64

Figure 11: Advice for patients at risk of Endocarditis, NICE CG64

Learning Bite

Routine antibiotic prophylaxis is no longer recommended.

Native valve disease with Streptococcal, HACEK or enterococcal infection has cure rates of 90%. Staphylococcal infections carry a worse prognosis with survival rates of 55-70% however Injectable drug users with right sided infections have better survival outcomes of 85-90%. Prosthetic valve infections carry a much higher mortality especially if infections occur in early convalescence.

Key Learning Points

• Infective endocarditis is a devastating illness which if untreated has high mortality rates, Level of evidence: 1
• People with pre-existing endocardial defects are predisposed, Level of evidence: 1
• Staphylococcus is the commonest isolated pathogen in endocarditis, Level of evidence: 1
• Diagnosis is based on modified Duke criteria, Level of evidence: 1
• Treatment requires prolonged injectable antibiotic use, Level of evidence: 1
• Urgent surgery can improve outcomes in selected groups of patients, Level of evidence: 1, 2
• Prophylaxis is not routinely recommended, Level of evidence: 1

1. National Institute for Health and Care Excellence. Prophylaxis against infective endocarditis: antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures. NICE guideline [CG64]. 2008. Updated in 2016.
2. Karchmer AW. Infective Endocarditis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. (eds.) Harrison’s Principles of Internal Medicine, 20e. McGraw Hill; 2018. [Accessed July 11, 2022].
3. Li JS, Sexton DJ, Mick N, Nettles R, et al., Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000 Apr;30(4):633-8.
4. Durack DT (ed): Infective Endocarditis. Infectious Disease Clinic North America. 2002; 16:255
5. Olaison L, Pettersson G. Current best practices and guidelines indications for surgical intervention in infective endocarditis. Infect Dis Clin North Am. 2002 Jun;16(2):453-75, xi.
6. Shively BK, Gurule FT, Roldan CA, et al., Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis. J Am Coll Cardiol. 1991 Aug;18(2):391-7.