Introduction

This is a condition caused by infection of the endocardium by bacteria, or rarely, fungus. It most commonly affects the heart valves (natural or prosthetic), but can occur anywhere along the lining of the heart or blood vessels.
It will most commonly occur at sites of previous damage, however, particularly virulent organisms (such as staphylococcus aureus and streptococcus pneumoniae) can infect previously normal areas of tissue; for example, Staph. Aureus will commonly infect the tricuspid valve in IV drug users.
In can present acutely or, more commonly, subacutely, where the symptoms may be more indolent and non-specific.

Epidemiology

50% of all cases of infective endocarditis will occur on normal valves. This type of infection tends to follow and acute course.
50% of infections occur on abnormal tissue, and these infections will tend to follow a sub-acute course.
The incidence in the UK is 4-7 per 100 000, although this is higher in the developing world

  • The disease is rare before the age of 55 in the UK
    • 4-7 per 100 000 in general population
    • 15 per 100 000 in the over 55’s

Without treatment, the mortality is close to 100%!

 

Risk Factors

Valvular damage

  • Previous Rheumatic heart disease (rare in the western world)
  • Age related valvular degeneration
  • Prosthetic valve (both mechanical and bioprostheses)

IV drug use

  • More chance of multiple organisms with IV drugs users. IV drug users are usually affected at the tri-cuspid valve, and the right side of the heart. Often the endocarditis is less clinically severe in IV drug users

Pathophysiology

Endocardial damage leads to the formation of thrombi at the damaged site. The thrombus is made mainly of platelets and fibrin. Initially these thrombi are sterile, and are sometimes called ‘sterile vegetations’. In normal circumstances, they usually heal within 24 hours.
The endocardial damage tends to occur around damaged valves, as aberrant jets of blood around these valves cause increased shearing forces in the endocardium, leading to endocardial damage. Also, the valve cusps themselves are avascular, and thus normal immune responses in this region are impaired.
These thrombi (and therefore IE) tend to occur at sites of high hemodynamic pressure, due to the increased shearing forces in these areas. Valves are also more likely to become fibrosed in areas of high pressure. Infections are not common at areas of low pressure, and thus IS most commonly occurs on the left side of the heart.
Transient bacteraemia exists in all individuals at some time. Common sources of bacteria include oral fauna, and genitourinary tract lesions. Therefore, poor oral hygiene and UTI’s are also risk factors.
Bacteria are able to colonise the thrombi, leading to infective endocarditis.
So essentially you require two factors:
  1. The presence of organisms in the blood – Many things can cause this. Common mechanisms include poor dental hygiene, IV drug use, soft tissue infection, and iatrogenic causes (including dental treatment, cannulae, cardiac surgery, and pacemakers).
  2. Abnormal / unusual endocardial tissue (most often the valve cusps themselves)
Once a thrombus has been colonised by bacteria, we call it a ‘vegetation’. These can become large enough to form an obstruction, or they may also break off to form emboli.
The emboli can affect pretty much any organ in the body (i.e. anything with a blood supply), but commonly affect structures that are highly vascularised, e.g. CNS, lungs, spleen, kidneys, liver. Therefore, common complications include e.g. splenic infarcts, PE. In sub-acute IE in particular,
IE is particularly hard to treat with antibiotics, because the platelets and fibrin in the vegetation prevent antibiotic agent, and white blood cells from being in direct contact with the bacteria.
  • Aortic and mitral valves are more commonly affected – because these exist in a higher pressure system than the tricuspid and pulmonary valves.
  • Right sided infection is more common in drug users – although the mechanism for this is poorly understood.
Also note that there are many rare causatory organisms (such as Haemophillus types), and that 5-10% of cases of infective endocarditis will be culture negative – because the causatory organism will not be able to be grown on normal blood cultures. In such cases, previous antibiotic therapy may be a factor – and this will need to be elicited in the history.

Signs and Symptoms

If the patient has a new murmur AND a fever – then it is endocarditis until proven otherwise
It can present as an acute infection, but more commonly presents sub-acutely with an insidious course. In this instance it is sometimes referred to as Sub-acute bacterial endocarditis (SBE)

Acute Presentation

Fever + new heart murmur (90%)
Petechiae (50%)

  • These are red/purple spots of 1-2mm diameter. They often form at sites of trauma, and in this instance they will usually disappear within a couple of days. Extreme bouts of vomiting, coughing or crying can also produce them around the eyes. They may also be a sign of a low platelet count (thrombocytopaenia).
  • In children they also may occur as a result of viral infection
  • They can be a sign of malignancy
  • Basically – lots of things can cause them!
  • They are non-blanching and essentially caused by bleeding under the skin.

Cardiac / renal failure can develop rapidly (50-70%)

  • Haematuria secondary to renal failure present in about 70% of patients

Rigors
Night sweats
Splinter haemorrhages (10-20%)

  • Red lines that run vertically along the nails. A non-specific sign, often associated with rheumatologic conditions as well as IE. In the case of IE, they are caused by small emboli.

Nail fold infarcts (5-10%)
Roth spots (5%)
Embolic incidents

  • Cerebral emboli (TIA/stroke) – 15%

Malaise (90%)

Sub-acute presentation

Typically, this will present in people with known congenital or valvular disease who are experiencing any of the above symptoms, and also possibly:
  • Fever
  • Rigors
  • Unknown murmurs
  • Splenomegaly (40%)
    • Coxiella infection – this particular bacterium will often caused a considerably enlarged liver and spleen
  • Clubbing (10%)
  • General fatigue
  • Purpura
    • These are basically the same as petechiae, except they are 3-10mm in diameter.
  • Osler’s nodes (rare) – these are painful swellings at the fingertips; commonly due to vasculitis.
  •   Palpable spleen
Patients may have had non-specific symptoms (e.g. malaise, low-grade fever) for several weeks or even months, and may not have any of the specific signs. Be wary of IE in patients with known valvular disease, and non-specific symptoms.
 
 

Textbook signs of IE

Below are further descriptions of some of the textbooks signs of IE. Remember, these are more common in sub-acute presentations, as they often take several weeks or months to develop. They are becoming less common in the developed world, as the condition is diagnosed earlier.
Janeway lesions
  • These are non-tender, small erythematous or haemorrhagic or nodular lesions on the palm or the sole, and generally about 2-4mm in diameter. They are specific for endocarditis.
  • Pathologically, the lesion is in the dermis, and made up of necrotic tissue with inflammatory infiltrate. The epidermis is not affected. They are caused by septic emboli.
  • Remember these are non-tender!
  • They occur most commonly in endocarditis that is staphylococcal in origin
Osler’s nodes
  • These are painful red lesions on the palms and sole. They are caused by immune complex deposition. This causes a localised immune response, resulting in a tender red swelling. They are usually indicative of IE, but can also be caused by SLE, gonococcal infection, infected arterial catheter.
The main difference between Osler’s nodes and Janeway lesions is that Osler’s nodes are tender and janeway lesions are not!
Petechiae
These are small (1-2mm) purple spots, caused by a minute haemorrhage. They can be caused by loads of things. They can be due to local trauma, and even more unusual trauma type events (e.g. lots of crying can result in petechiae around the eyes) but can also be a sign of something more significant. They are most commonly caused by trauma, but if you see them you should try to find out more about them and not just dismiss them straight off! They may be present in:
  • Vasculitis – this is probably the cause in IE. In IE petechiae are most commonly seen in the conjunctiva
  • Thrombocytopaeina – low platelet count
  • Malignancy
  • Viral infection – particularly in children
  • Leukaemia
  • Typhus
Roth spots
These are retinal haemorrhages will a pale or yellow centre.

Post-operative endocarditis

Any fever in a patient who had had heart / valve surgery should be investigated for endocarditis. The infection tends to affect the valve ring and can resemble either acute or subacute endocarditis.
The most common causatory organism in these cases is staph epidermis – which is a normal skin bacteria. It if often present in blood cultures, but dismissed as contamination.
Causatory Organisms
Staphylococcus Auerus is the most common causatory organism. Gram-positive tend to be more common than Gram-negative, because Gram- positive have better adherence to endocardium.
  • Q fever – this is disease caused by coxiella burnetti and is most commonly found in people who have been working with farm animals; it is also found in cats and dogs. It is highly infectious. It most commonly affects the aortic valve, and there may be liver complications and purpura. Life-long antibiotic therapy may be required.
  • Gram-negative bacteria from the ‘HACEK’ group (haemophilus, Kingella, eikenella) are slow growing, and generally resistant to penicillin.
  • Brucella is associated with contact with goats, and will often affect the aortic valve.
  • Yeasts are most common on immuno-compromised individuals, IV drug users, or those with IV lines. There may be abscesses and emboli, and often co-existing bacterial infection. The prognosis is extremely poor, and surgery will often be required.

Diagnosing IE

For definitive information on making a diagnosis, we have the Duke criteria. This divides symptoms into two categories; major and minor criteria:

Major criteria

  • Positive blood culture for infective organisms (on 2 separate tests if >12 hours apart, or on 3/3 or 3/4 tests >1 hour apart)
  • Evidence of IR from other tests:
    • Echocardiogram shows:
      • strictures, unusual blood flow, implanted /unusual material
      • Abscesses
  • New valve regurgitation

Minor Criteria

  • Fever >38’C
  • Predisposition to IE; e.g. IV drug user, congenital heart condition, prosthetic valve
  • Unusual echo, but not with findings stated above
  • Immunological factors present; Roth spots, Osler’s nodes, glomerulonephritis, rheumatoid factor
  • Blood cultures positive, but major criteria not satisfied
  • Vascular abnormalities; embolism, aneurysm, infarcts, conjunctival haemorrhage, intracranial haemorrhage etc
You can then assess whether IE is present or not:
  • IE definitely present:
    • 2 major criteria present OR
    • 1 major criteria, 3 minor criteria OR
    • 5 minor criteria
  • IE possibly present:
    • 1-4 minor criteria AND
    • No other more likely diagnosis

Echocardiography

TTE – transthoracic echocardiography – this is rapid and non-invasive, and has a high specificity for visualising vegetations, however, the sensitivity is only 60-70%. Generally vegetations of above 2mm can be seen, but ones smaller than this are easily missed. Also, it can be difficult to distinguish between an abnormal valve, and an abnormal valve covered in vegetations.
Transoesophageal echo (TOE) may identify vegetations of 1mm and bigger in diameter. This investigation is particularly useful in those with prosthetic heart valves. Thus this test has a higher sensitivity of 90%. It also provides a better view of prosthetic valves, and thus is the choice of test for those with these.
Just because you don’t identify vegetations on the echo, does not mean they are not present, and this should not delay treatment!

Microbiology

You need to take a minimum of 3 samples within 24 hours, most places recommend a minimum of 6. Make sure you take the first sample before AB therapy has begun. Also remember the general rules when sending off samples – give as much information with the sample as possible to help the lab identify what it may be, take the samples from different sites, aim to avoid contamination, and do not use an existing line to take samples.
  • Note that in some cases the causatory organism will not grow in blood cultures. So in cases where you have negative blood cultures, you need to send serology tests to check for organisms. These organisms include; coxiella, bartonella, legionella and chlamydia.
  • Giving antibiotics before taking samples can result in negative samples, despite the presence of a causatory organism
  • Always check the CRP and WCC if you suspect infection. If CRP and WCC are normal, yet you have a positive blood culture, the positive culture is likely due to contamination.

Other lab tests

  • Full blood count- A normocytic, normochromic anaemia (anaemia of chronic disease) may be present, as are polymorphonuclear leucocytes. Thrombocytopaenia (low platelet count) and thrombocytosis (high platelet count) are also common.
  • U+E- Renal dysfunction is common
  • LFT’s- ALP is likely to be raised, other values may be slightly abnormal
  • Inflammatory markers – CRP and ESR are likely to be raised. CRP is a more acute phase protein than ESR, and thus is more accurate and useful in monitoring progress.
  • Immunoglobulins and complement – Ig’s will be increased, but complement decreased, because there is increased immune complex formation. This test is not routinely performed, but results will be abnormal in 70% of cases.
  • Urine – proteinurea may occur, and microscopic haematuria is nearly always present
  • PCR – rare – polymerase chain reaction – this is used in cases where a blood culture has not produced any growth, but IE is still highly suspected. It is a technique that can extract DNA and RNA from any tissue or blood sample.

ECG

May show signs of MI and conduction defects. A new AV block is suggestive of abscess formation. This test should be performed on admission, and throughout the hospital stay to check for new changes.

CXR

May show evidence of heart failure and cardiomegaly. In right sided heart failure there may be pulmonary emboli and / or abscesses. A combination of sepsis and pulmonary infiltrates on the CXR is highly suggestive of right sided endocarditis.

Treatment

This is generally difficult because the organisms are in a protected environment within the vegetations. The layers of fibrin and platelets in the vegetation can prevent both immune cells and antibiotics from coming into direct contact with the bacteria. High concentrations of antibiotics are required for prolonged periods of time for any success. Usually a combination of agents is used, depending on the organism present.
The general mortality for endocarditis is 20-30%. This increases in the case of prosthetic valves and those infected with resistant organisms.
The source of infection (e.g. a tooth with an infected abscess) should be removed as soon as possible.
The best outcomes are achieved when there is a multi-disciplinary team approach.

General recommendations

  • Acute presentation – flucloxacillin, gentamycin
  • Subacute presentation – benzylpenicillin, gentamycin
  • Prosethetic valve / resistant organism – triple therapy of vancomycin, gentamycin and rifampicin
In cases of penicillin allergy, then vancomycin (a glycopeptide – other example is teicoplanin) is the usual substitute. Penicillins are fundamental to effective treatment, and thus generally those with penicillin allergy have a worse prognosis. Thus it is more important than even to clarify what the patient means when they say they have an allergy to penicillin. An upset stomach is not an allergy!
You should give antibiotics as soon as the blood samples have been taken, and then adjust the regimen in accordance with the results. There is an exception to this, in that you should not give any antibiotics to someone who has recently taken antibiotics until you have the blood results, as you don’t want to confuse the picture even more with further antibiotics.

Surgery

This is becoming a more popular method of treatment. Between 25-50% of patients will be treated surgically. This will usually involve valve replacement, although sometimes just partial valve repair is performed. These operations will remove the focus of the infection, and hopefully cure the disease
Indications for surgery:
  • IE resistant to antibiotic treatment
    • Often Gram-negative disease
  • Fungal disease resistant to treatment
  • IE causing embolic events
  • IE with CHF
  • Severe structural damage on echo
Each case needs to be considered individually, with both cardiologists and cardiothoracic surgeons. Essentially, it is the most severe cases, with the most structural damage that require surgical therapy.
The surgery itself has a mortality of 8-16%, and long-term mortality is between 1-30%, thus outcomes are variable, but probably similar to antibiotic therapy.

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