Infective endocarditis is a microbial infection of the endocardium. It is a serious and life-threatening disease which is uncommon in childhood. Endocardial infections were formerly known as bacterial endocarditis, but the term infective endocarditis is used in order to encompass both bacterial and fungal causes. The term may also be used to describe infections of the arterial duct, surgically created shunts such as a classical or modified Blalock-Taussig anastomosis, and infection at the site of aortic coarctation, although infective endarteritis would be a more accurate term for this group.
EPIDEMIOLOGY
Prevalence and Incidence
Infective endocarditis is less prevalent in children than in adults, although its incidence in children may be increasing. 1,2 This is in part due to the increased incidence of infective endocarditis in patients with congenitally malformed hearts who are now surviving longer. The epidemiology of infective endocarditis in developed countries has changed. There has been an increase in the survival of children with congenitally malformed hearts, along with a decline in prevalence of rheumatic heart disease, so that in most countries congenital cardiac disease is now the most common substrate for infective endocarditis.
Subsequent to surgical correction of complex congenital cardiovascular malformations, patients have a long-term risk of infective endocarditis, although in up to one-tenth of cases seen in children, no structural cardiac disease or identifiable risk factors exist. 3 The condition in such cases commonly involves infections of the aortic or mitral valves in the setting of bacteraemia due to Staphylococcus aureus 4,5
The incidence of neonatal endocarditis is also increasing. 6,7 The rate of death in this age group is high, and often the diagnosis is made after death. Early repair of congenital malformations of the heart in neonates and infants has increased the prevalence of perioperative infective endocarditis in this age group. 5 The increased use of indwelling intravenous lines and implantable devices, along with the evolution of more advanced neonatal and paediatric intensive care, has increased the risk of endocarditis related to catheters. 2,7 Indwelling catheters may also predispose to the development of endocarditis in children with cancer. 8
These changing patterns of infective endocarditis have not occurred in many poor or underdeveloped parts of the world. Rheumatic fever in these countries is still common, and access to congenital cardiac surgery is limited. 9 Rheumatic disease of the mitral and aortic valves, therefore, remains the most common basis for infective endocarditis globally. Abuse of intravenous drugs and degenerative diseases of the heart, which are important causes of endocarditis in adults, are not common predisposing factors in children.
Mortality
Infective endocarditis was universally fatal prior to the introduction of antibiotics. When sulphonamides were introduced, a small proportion of patients were successfully treated. A larger proportion of patients was cured with the introduction of penicillin, when about two-thirds survived the infection, with further increases in survival in more recent decades. 10 This reduction in mortality and morbidity has been due to advances in antimicrobial therapy, early detection of endocarditis, aggressive management of its complications, and improvements in surgical techniques. 10 Despite these improvements, between one-tenth and one-quarter of those suffering endocarditis may still die. 11,12
PATHOGENESIS
Intact endothelium is resistant to colonisation by microorganisms. Injury or erosion to the endothelial surface, which can occur from haemodynamic or mechanical stress, is a potent inducer of thrombogenesis. The initial deposition of platelets and fibrin over the damaged endothelium is referred to as a nonbacterial thrombotic endocarditis. This is the crucial lesion, which provides a surface for bacteriums to stick to the endothelium, leading to the development of infective endocarditis. 13 When microorganisms enter the bloodstream, colonisation on the altered endothelial surface will ultimately convert the nonbacterial thrombotic endocarditis to infective endocarditis. Trauma to the oral mucosa, particularly the gums, the genitourinary tract, and the gastrointestinal tract are especially associated with increased risk of bacteraemia.
The propensity to adhere to the nonbacterial thrombotic endocarditis depends on the type of microorganism. Gram-positive organisms, such as enterococci or viridans streptococci, have the propensity to adhere to valvar surfaces, whereas gram-negative bacilli, such as Klebsiella , do not adhere well. 14 Gram-positive microorganisms, therefore, are the predominant organisms in endocarditis. Other bacterial factors, including dextran produced by the Streptococcus viridans , have been identified as promoting adherence to heart valves. 15 Furthermore, the interactions of gram-positive organisms with platelets, and their capacity to resist the antimicrobial properties of platelets, are pivotal to the development and persistence of endocardial infections. 16
The defenses of the host play a major role in the onset of infective endocarditis. In children with cardiac disease, the shear forces associated with a stream of blood with high velocity can damage the endothelium. In damaged valves, the local pattern of flow is altered as a result of changes in the geometry of the valve. Indwelling intravenous catheters positioned in the right side of the heart may traumatise the endocardium, commonly that on the valves, exposing the subendothelial collagen. 17 These factors promote the development of non-bacterial thrombotic endocarditis, allowing adherence of microorganisms during bacteraemia, and the onset of infective endocarditis. Microorganisms, in turn, promote the further deposition of platelets and fibrin, thus enlarging the vegetation ( Fig. 55-1 ). Organisms within the vegetation are protected from the defense mechanisms of the host, which allows them to proliferate rapidly. 18,19
INFECTIVE ENDOCARDITIS IN THE CONGENITALLY MALFORMED HEART
Congenital cardiac disease is now the major underlying condition predisposing to infective endocarditis during childhood in developed countries. The incidence of infective endocarditis in this group is increasing 5 as more children with congenital cardiac disease survive surgical interventions. Many such patients will have undergone previous cardiac surgery. At highest risk are those who have had repair or palliation of cyanotic disease. 20
Site of Infection
It has long been known that endocarditis commonly occurs when blood is driven from a source of high pressure, for example, the left ventricle or aorta, through a narrow orifice, for example, aortic coarctation, a small ventricular septal defect or arterial duct, or a regurgitant aortic or mitral valve, at high velocity into a low pressure sink, for example, the atrium, pulmonary trunk, or right ventricle. 21 It has been suggested that the high velocity of the stream of blood immediately beyond the orifice leads to a marked drop in the hydrostatic pressure laterally, so that, consequently, the perfusion of the endothelial intima at this level is reduced. This is then the characteristic site of the infective process. This so-called Venturi effect accounts for the finding that it is the left atrial side of the mitral valve that is affected in mitral incompetence, while in a ventricular septal defect, infection is usually centred on the right ventricular surface of the septum ( Fig. 55-2 ). Small defects are nearly always involved, as large defects dissipate any differences in pressure. Similarly, in an arterial duct, it is commonly the pulmonary arterial end that is infected, while in aortic incompetence, it is the ventricular surface of the leaflet that is involved.
Infective Endocarditis in Unoperated Congenital Heart Disease
The lesions which are most commonly affected by infective endocarditis are small ventricular septal defects, aortic stenosis or incompetence, tetralogy of Fallot, and persistently patent arterial ducts. 22 Conversely, there have been only a few reports of endocarditis possibly related to isolated defects of the atrial septum, although patients with the so-called ostium primum defect, in reality an atrioventricular septal defect with separate valvar orifices for the right and left ventricles, may be affected. 23,24
In children aged between 5 and 14 years with a ventricular septal defect, the estimated risk is 1 in 500 patient-years, or two infections per 100 patients over a period of 10 years. 25 The risk is increased considerably when there is associated aortic incompetence, or in the setting of defects producing a shunt from the left ventricle to right atrium. When infective endocarditis occurs in those with tetralogy of Fallot and pulmonary atresia, it is usually the aortic valve that is affected. This is also the case in tetralogy with pulmonary stenosis, although the pulmonary valve can also be affected. Prolapse of the mitral valve remains an important underlying cause in children in whom no cardiac anomaly was suspected prior to the development of infective endocarditis. This is also the case in older patients with aortic valves having two leaflets. Infective endocarditis in patients with hypertrophic cardiomyopathy is virtually confined to those with obstruction to the outflow tract, and is more common in those with both obstruction and atrial dilation, 26 although this rarely occurs in childhood.
Infective Endocarditis after Surgery for Congenital Cardiac Disease
When defects such as a ventricular septal defect or the persistently patent arterial duct are completely repaired without residual sequels, the risk of endocarditis is reduced to that for the normal population by 6 months after surgery. 5 For some patients, however, the risks of infective endocarditis may be increased by cardiac surgical procedures, particularly after palliative surgery involving insertion of conduits or creation of shunts to relieve obstruction to the flow of blood to the lungs, and after replacement of the aortic valve with a prosthesis. The risk for infective endocarditis is particularly high in the immediate postoperative period, especially where prosthetic valves or conduits have been used during the repair, or when haemodynamic problems persist. 27
MICROBIOLOGY
Gram-positive organisms are most commonly responsible for infective endocarditis in children, particularly, streptococcuses, staphylococcuses, and enterococcuses. 28
Streptococcus
Streptococcus of the Viridans or α-Haemolytic Group
These organisms, which exhibit so-called α-haemolysis on blood agar plates, were responsible for more than nine-tenths of cases before the widespread use of antibiotics. 29
Oral Streptococcus Group
The species that most commonly cause endocarditis are Streptococcus sanguis , Streptococcus oralis , also known as mitis , Streptococcus salivarius , Streptococcus mutans , and Gemella morbillorum , formerly called Streptococcus morbillorum . These organisms form part of the normal flora of the mouth and the upper respiratory tract and are almost always susceptible to penicillin G.
Streptococcus milleri Group ( Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus )
Infection with these organisms has the tendency to form abscesses, which disseminate through the bloodstream, for example, visceral abscesses and osteomyelitis.
Abiotrophia defectiva and Infective Endocarditis Produced by Granulicatella Species
These agents were formerly known as nutritionally variant streptococci. The strains have nutritional deficiencies that hinder their growth in standard culture media. They often exhibit tolerance to penicillin.
Staphylococcus
Coagulase-positive species, such as Staphylococcus aureus , or species which are coagulase negative, such as Staphylococcus epidermidis and others, can cause infections in both native and prosthetic valves, indwelling vascular catheters, and prosthetic materials. They are predominantly very resistant to penicillin G and to ampicillin, due to the production of enzymes called β-lactamases
Staphylococcus Aureus
This is one of the most common organisms responsible for infective endocarditis in children. It has virulent properties, and is associated with acute bacterial endocarditis. The organism has the ability to affect normal valves, especially in patients with impaired immunity. Advances in invasive medical treatments, and in particular the increased use of intravascular devices, have resulted in an increased incidence of this form of endocarditis. 30
Enterococcus
Enterococcus is responsible for endocarditis less frequently in children than in adults, accounting for about one-twentieth of isolates from blood cultures. Faecal organisms are normal commensals in the gut, genitourinary tract, and sometimes the mouth. 31 In older patients, endocarditis may follow procedures within the genitourinary tract, such as urethral catheterisation, abortion, normal delivery, and even insertion of an intra-uterine contraceptive device.
Other Bacterial Organisms
Infection from Streptococcus pyogenes was formerly associated with an acute fulminating infection following erysipelas. Infection by this organism is now uncommon, presumably related to the early use of antibiotics in this condition. Similarly, infection with Streptococcus pneumoniae was a recognised complication of pneumococcal meningitis or lobar pneumonia, although it is rare following the introduction of antibiotics. Patients with right isomerism and asplenia are still at risk from this infection.
Gram-negative organisms very rarely cause infective endocarditis in children. Neisseria gonorrhoeae can cause a fulminating endocarditis, but it is not a major problem in children in the current era. Pseudomonas aeruginosa can cause infection in patients on intensive care units, particularly those with indwelling catheters.
Less frequently, endocarditis can be caused by fastidious gram-negative organisms of the so-called HACEK group, specifically, Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus, Haemophilus influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, and Kingella denitrificans 32
Fungal Endocarditis
Fungal endocarditis is rare, but its incidence appears to have increased significantly in recent years due to advances in medical technology. Risk factors include the requirement for prolonged intravenous catheterisation or use of antibiotics, dialysis, hyperalimentation, and immunosuppression, as well as surgical procedures which require implantation of prosthetic devices such as heart valves and pacemakers. 33 The organisms are usually candidal species although aspergillus has been reported. Up to three-quarters of those suffering fungal endocarditis still die. The typical large and friable vegetations contribute to the higher rates of complication. Delay in diagnosis is common and may contribute to the high rates of death. 34
CLINICAL FEATURES
In paediatric practice, it is still useful clinically to distinguish between acute and subacute presentation. Often no precipitating event or primary focus of infection is found in children. When one is found, dental extractions, orthodontic procedures, or other dental manipulations are the most common. 35 Cardiac catheterisation rarely causes endocarditis, although staphylococcal infection may occur especially at the site of entry of the catheter. The increased use of indwelling intravascular catheters and implantable devices has resulted in many catheter-related infections, bacteraemias, and device-related infections. Endocarditis may follow cardiac surgery, particularly when an artificial material such as external conduit or prosthetic valve is used.
The defense mechanisms of the host, along with the virulence of the infecting organisms, determine the clinical manifestations. Other important factors include the type of valve infected, whether native or prosthetic, whether the infection was acquired in the community or in hospital, and if previous antimicrobial therapy was used. The indiscriminate use of antibiotics in children with congenitally malformed hearts is ill advised unless a genuine cause of illness or pyrexia is found. These factors increase the variability with which infective endocarditis can present. In some patients, infective endocarditis may mimic a wide spectrum of disorders, ranging from other infections to malignancies or diseases of connective tissue. The clinician requires vigilance in keeping infective endocarditis in mind, particularly when a patient with known cardiac disease has an unusual febrile illness, as any delay in diagnosis may lead to a higher rate of complications.
Non-specific Features
Fever
Fever is the most common symptom in patients with endocarditis, particularly in those outside the neonatal period. The fever is initially continuous, but may become recurrent and low grade with asymptomatic intervals, particularly if short courses of antibiotics were given. A low-grade fever is the predominant symptom in the classical presentation of subacute bacterial endocarditis, which is typically caused by the viridans group of streptococcuses. Infection with Staphylococcus aureus often causes very high fever. The fever is usually accompanied by a variety of somatic complaints, including fatigue, weakness, arthralgias, myalgias, anorexia, weight loss, rigors, and diaphoresis.
Arthralgias and Arthritis
These features are typical of subacute infective endocarditis, so that it may mimic rheumatologic diseases. Sometimes there is arthritis of a single joint, but more commonly there is generalised arthralgia. 36,37
Cardiac Features
Congestive Cardiac Failure and Valvitis
Increasing breathlessness and tachycardia may reflect cardiac failure and/or anaemia. Cardiac failure may result from both mechanical and myocardial factors. Valvar involvement may result in destruction of the aortic or mitral valves causing severe regurgitation. Embolism to the coronary circulation may produce myocardial infarction, while occasionally a diffuse myocarditis may also contribute to myocardial dysfunction.
Embolisation
Embolisation of infected or thrombotic material from cardiac vegetations may lead to ischaemia, infarction, or mycotic aneurysms. The site of embolism determines the clinical findings. In patients with endocarditis involving the right side of the heart, embolisation may be misdiagnosed as pneumonia in a patient who presents with chest pain and breathlessness. Typically, the chest radiograph demonstrates multiple, scattered, fluffy infiltrates, which disappear and then reappear on serial films. 38 Vegetations on the mitral valve appear to be particularly associated with a high risk of embolisation. When such embolisation occurs, any organ can be affected. Splenic infarcts present with features typical of an acute abdominal problem.
Neurological Complications
Neurological complications or manifestations are common, being found in more than one-third of patients. 39 These may result from embolisation to the central nervous system, which may result in a stroke or diffuse cerebral vasculitis, which results in a confusional state, headache or psychiatric disturbance. Rarely, mycotic aneurysms within the central nervous system can occur. Their rupture can be catastrophic ( Fig. 55-3 ).
Renal Abnormalities
Renal involvement is most common in patients with staphylococcal infections, resulting in haematuria, glomerulonephritis, or renal infarction, which may occur in up to half of such patients. 40,41
Physical Findings
Patients appear ill, with a fever. Splenomegaly is present in two-thirds. It is often painless unless the spleen is greatly enlarged. There may be hepatomegaly and other signs of heart failure. Anaemia is common. The auscultatory signs of valvar regurgitation should be carefully sought. The child may have a cardiac anomaly with preexisting murmur. Frequent examinations are necessary if infective endocarditis is suspected, since a change in murmur is one of the classical features of the disease. The classical extracardiac manifestations of infective endocarditis, such as petechial haemorrhages, Roth’s spots, Janeway lesions, Osler’s nodes, and splenomegaly, are all rare in children.
INFECTIVE ENDOCARDITIS IN THE NEWBORN
Infective endocarditis affecting the newborn commonly occurs in those born prematurely, particularly after a period of prolonged hospitalisation. 42 The incidence appears to be rising, in part due to the increased survival of such premature infants with indwelling catheters, 43 but also due to increased recognition of endocarditis by the application of cross sectional echocardiography. Infections usually involve the right-sided cardiac structures in babies who have structurally normal hearts. Less than one-third of cases of neonatal endocarditis occurs in the presence of congenital cardiac disease. 44 The most common infecting organisms are Staphylococcus aureus , coagulase-negative staphylococcuses, and Candida species.
The signs are usually non-specific, particularly in the preterm neonate. Many infants have feeding difficulties, respiratory distress, and tachycardia. Fever is seldom a major feature. Neonates may present with septicaemia, hypotension, congestive cardiac failure, or a changing murmur. Neurological signs and symptoms such as seizures, hemiparesis, and apnoea occur in many infants. Septic embolisms are common, and cause focuses of infection outside the heart, such as osteomyelitis, meningitis, and pneumonia.
LABORATORY DIAGNOSIS
Cultures of Blood
Cultures of blood are of paramount importance in order to isolate the infecting organism. The identity of the organism may suggest the source of bacteraemia, for example, isolation of Streptococcus viridans points to an oral source. Based on the organism’s sensitivity to antibiotics, initial antibiotic therapy may be corrected, which has been shown to reduce mortality. 45 Blood should be cultured from all patients with fever of unexplained origin and a pathological murmur, a history of cardiac disease, or previous endocarditis. The last indication is because a previous episode of endocarditis is a risk factor for a further episode. 46 Bacteraemia in patients with infective endocarditis is usually continuous. It is not necessary, therefore, to obtain the cultures at any particular phase of the fever cycle. One set of cultures, while better than none, is not sufficient, as it does not demonstrate the continuous nature of the bacteraemia, nor does it maximise the chances of isolating the organism and differentiating between contamination and true bacteraemia. 47 In most units, two or three cultures through separate venipunctures on the first day is considered to be adequate. In the critical situation of acute infective endocarditis, where prompt treatment is crucial, cultures can be obtained within 5 minutes of each other prior to the administration of empiric antibiotic therapy. Pathogens will be grown in cultures in well over seven-tenths of untreated patients, but only from three-fifths of those in whom antibiotics were used before the sample was taken. 48 Further cultures are necessary when results are negative and the clinical suspicion of endocarditis is high, particularly if antibiotics had been given prior to sampling.
False-positive results can be due to contamination by skin flora, or from samples obtained from contaminated intravascular catheters. Such false-positive results can be averted by optimal preparation of the skin before venipuncture. Whenever possible, samples from indwelling catheters should be not be used. 49 Adequate volumes of blood should be obtained. The volume of blood taken should be as large as reasonably possible for the size of the child. Both aerobic and anaerobic cultures should be obtained, though anaerobic cultures are not necessary for all sets.
Other Tests
It is important to determine the sensitivity of the organism to antibiotics and to measure the so-called minimum inhibitory concentration to optimise the choice of antibiotics. Anaemia is common, particularly in those with chronic disease. The number of white cells in the blood is typically elevated, with a preponderance of polymorphonucleocytes. More than nine-tenths of patients will have at least microscopic haematuria. Haematuria with red blood cell casts, proteinuria, and renal insufficiency may indicate the presence of glomerulonephritis. Elevated levels of acute phase reactants, specifically the rate of erythrocytic sedimentation and levels of C-reactive protein, are common.
In patients who undergo surgery for endocarditis, resected cardiac tissue may be helpful in the identification of so-called fastidious organisms, 50 although it has also been shown that the rate of contamination of such specimens may be high. 51 Amplification of specific bacterial sequences of desoxyribonucleic acid using polymerase chain reaction has also been used for the analysis of blood and tissue samples, 52,53 although this technique is not routine in most laboratories. Cultures of cells may be of use in the identification of intracellular organisms, such as Bartonella or Coxiella , 54 while serological methods may play a role in the identification of infections with these organisms and others. 54
IMAGING STUDIES
Echocardiography
Echocardiography is the primary modality for the detection of vegetations and cardiac complications from endocarditis. It can demonstrate the site of infection and extent of damage. Serial assessments can follow the course of infection. Cardiac and valvar function can be monitored and the response to therapy assessed. 55
Typical echocardiographic findings include the presence of vegetations ( Fig. 55-4 ), abscesses, and new valvar insufficiency. Vegetations are usually seen on the upstream side of the valve, that is, on the atrial side of the atrioventricular valves, on the ventricular side of the arterial valves, and at the points of impingement of high-velocity jets on the valve or cardiac wall. In those with prosthetic valves, vegetations can arise from the prosthetic ring and/or along the edge of the site of a jet with high velocity. The size of the vegetation is likely to predict the likelihood of embolisation, particularly when it is on the mitral valve. 56,57
