Infective Endocarditis in Congenital Heart Disease

Abstract

Any congenital heart disease (CHD) with high-velocity jets of blood flow and/or artificial material is associated with the highest risk of infective endocarditis (IE). And IE can be a big issue not only for the patient with CHD before the operation but also after the palliative and the radical surgery. Jets stream of the intracardiac shunt (including the residual shunt after corrective operation) and artificial conduits and/or patches after palliated or corrective operation can be the origin of IE. Even though the incidence of IE in children is much lower than in adults, the risk of IE can be high for patients with CHD. Certain CHD are common underlying conditions of IE, including ventricular septal defects, patent ductus arteriosus, aortic valve abnormalities, endocardial cushion defects, and tetralogy of Fallot. Furthermore, patients with complex cyanotic CHD with or without conduit procedures, palliative shunt, patches, and prosthetic valves are becoming a large group at risk.

1. Introduction

Many of congenital heart diseases (CHD) have become manageable because of the progress of medical and surgical approaches and the improvement of prosthetic materials over the past few decades. Infective endocarditis (IE) can be a big issue not only for the patient after the radical surgery but also after the palliative surgery and before any operation. Because most of them have a condition that can predispose them to IE, including valve regurgitation, jet flow of intra/extracardiac shunt, and prosthetic material. Even though the number of cases of IE in children is small compared to adults, recent reports have pointed out a tendency that the incidence of IE among children is increasing due to the improving survival rate of patients with CHD [1, 2, 3] and more frequent use of implanted prosthetic material [4, 5, 6, 7].

2. Epidemiology

Now CHD appears to be the predominant underlying condition for IE, especially in children over 2 years old [2, 4] and age of IE gets younger because of early advanced treatment [8, 9]. Pediatric IE related to CHD accounts for 74–88% of the total pediatric IE [10, 11]. Age distribution seems with a peak in infancy during childhood [1, 8, 11, 12].

In children with CHD, the cumulative incidence of IE has been estimated at 6.1 per 1000 patients, and overall incidence rates of IE are 4.1 to 11.13 per 10,000 person-years [8, 13, 14]. And children with CHD have an estimated 15–140 times higher risk of developing IE compared to the general population [10]. The lesion group-specific cumulative incidence of IE was reported as follows: cyanotic CHD, 31.0–35.73; atrioventricular septal defect, 11.1–27.24; left-sided lesions (e.g., coarctation of the aorta, aortic stenosis/insufficiency, mitral stenosis/insufficiency), 7.9–14.3; ventricular septal defect, 3.2–10.1; right sided-lesion (e.g., Ebstein’s anomaly, tricuspid valve disease, anomalous of pulmonary valve/artery), 3.0–4.2; atrial septal defect, 2.8–3.0; and patent ductus arteriosus, 1.5–3.2 [8, 13].

IE is a serious problem not only for pediatric CHD but also the adult CHD. An increasing number of children reach adulthood because of the improvement in medical and surgical procedures. The number of adult CHD patients is now exceeding number of children with CHD, and they are the much more vulnerable to IE due to greater cardiac complexity and higher rates of comorbidities compared to a few decades ago [3]. The overall incidence of endocarditis in adults with CHD has been reported to be 11 per 100 000 person-years, and this incidence is three times higher than in children with CHD [15] and which is a considerable increase compared with the general population, in which a rate of 1.5 to 6.0 per 100 000 patient-years [15, 16]. In general, IE is correlated with age, and patients with CHD have a similar IE incidence as that of 81-year-old control. But by the age of 40–65 years, the IE incidence is more than 75–100 times higher in patients with CHD than in controls [17, 18]. And the risk of adult CHD was 2.5 times higher in children with CHD [18].

Overall inpatient mortality of IE in patients with CHD is estimated at 5.0–6.7% in children [1, 13] and up to 8.8–15% in adults [14, 18], and mortality of IE patients with cyanotic CHD is 3.6 times higher than that of the IE patients with non-cyanotic CHD [13]. Mortality rate is up to 48% in patients with tetralogy of Fallot and pulmonary atresia and 9.9% in patients of tetralogy of Fallot without pulmonary atresia.

3. Risk factors

All vegetations occur in areas where there is a pressure gradient with resulting turbulence blood flow [3]. Congenital heart disease with high- velocity jets of blood flow and/or artificial material is associated with the highest risk of IE. Any lesion associated with turbulence of blood flow, with or without shunting, can be a basement for IE [2]. Certain CHD are still common underlying conditions of IE, including ventricular septal defects, patent ductus arteriosus, aortic valve abnormalities, endocardial cushion defects, and tetralogy of Fallot [8, 19, 20]. Furthermore, patients with complex cyanotic CHD with or without conduit procedures, palliative shunt, patches, and prosthetic valves are becoming the large group at risk [2], even though mechanisms of cyanosis on the pathogenesis of IE are not clear [9]. On the other hand, in secundum atrial septal defect which has no high-velocity jet flow shunting, and in mild pulmonic stenosis, endocarditis is not likely to occur [2, 20].

Turbulent blood flow from a high-to low-pressure chamber or across a narrowed orifice traumatizes the endothelium. Thrombogenesis can occur on the damaged endothelium easily and results in the disposition of sterile clumps of platelets and fibrin and the formation of nonbacterial thrombotic endocarditis [3]. This provides an environment to which bacteria can adhere and eventually form infected vegetation. This endothelial lesion is usually located at the low-pressure end of an abnormality with a large gradient and most vegetations are found on the atrial side of the atrioventricular valves and downstream in the descending aorta in coarctation of the aorta [3, 21]. An exception is valvular aortic stenosis. The vegetation occurs often on the ventricular side of the aortic valve. A possible explanation is that almost all aortic valvular stenosis is accompanied by some degree of aortic insufficiency [3]. And an aortic regurgitant jet or prolapsing aortic vegetation can affect the anterior mitral leaflet causing secondary vegetation [21].

Approximately 50–70% of IE in children with CHD have had previous cardiac surgery, particularly palliative shunt, or complex corrective surgery [3, 4, 13]. Prosthetic material with higher surface tension (e.g., polyethylene, terephthalate) exhibits higher binding capacity for fibrinogen, a hydrated macromolecule, than material with lower surface tension (e.g., fluorocarbon polymers) and is more prone to initiate IE [9]. Even though complete repair of CHD with sufficient endothelialization after 6 months of procedure may eliminate the risk for IE, patients are at high risk before complete endothelialization. Patients who had undergone cardiac surgery in the prior 6 months are more than 5 times more likely to develop IE compared to patients without cardiac surgery [8, 13]. Among the invasive procedure, shunt surgery is associated higher risk of developing IE within the 6 months after procedure [13]. In addition, postoperative IE is a long-term risk even after corrective surgery, especially in those with residual defects, surgical shunt, and other prosthetic material [4, 9].

The progress of transcatheter placement of devices such as septal or vascular occluders, vascular occluders, and coils can be another risk factor for IE. Generally, IE occurs particularly in the early post-deployment period before endothelialization especially within 6 months [4, 13], and it is rare to occur after complete endothelialization. And it is suggested that IE after transcatheter device treatment is related to residual defects or shunts after device deployment [22].

Pulmonary valve implantation is often required in patients with CHD, and transcatheter pulmonary valve implantation is increasingly being used. Multiple studies which analyzed the occurrence of IE in surgically and transcatheter implanted bovine jugular vein pulmonary conduits, such as Melody valve stents and Contegra conduits, reported an increased incidence of IE compared to other valve types [23, 24, 25]. Annualized incidence rates of IE in homografts, Contegra and Melody valves were 0.40%, 0.97%, and 6.96% 1 year and 0.27%, 1.12%, and 2.89% 5 years after valve implantation [24]. And a systematic review reported that the median cumulative incidence of IE was higher for bovine jugular vein valve compared with other valves (5.4% vs. 1.2%) and the incidence of IE was not different between surgical and catheter-based valve implantation. They concluded that this result suggested that the substrate for future infection is related to the tissue rather than the method of implantation [25].

Several predictors for IE in adult CHD patients are identified. Foremost among these predictors are recent (<6 months) medical interventions including genitourinary, gastrointestinal, and respiratory procedures (Odds Ratio 12.52), recent (<6 months) cardiac surgery (OR 9.07), male sex (OR 2.07), and diabetes mellitus (OR 1.65) [18]. And previous IE is a substantial risk factor of recurrent IE [9]. Regarding CHD lesions, endocardial cushion defect (OR 6.65) and left-sided lesions (including aortic coarctation, aortic stenosis/insufficiency, mitral stenosis/insufficiency) (OR 5.11), cyanotic CHD (OR 4.82), and ventricular septal defect (OR 2.81) are at higher IE risk. Because ventricular septal defect is the most frequent CHD, it can be the most frequent CHD-associated IE if unrepaired [9]. And right-sided lesions (including Ebstein’s disease, anomalous pulmonary artery/valve, and tricuspid valve disease), atrial septal defects, and patent ductus arteriosus are at lowest IE risk [18]. Patients palliated by an aortopulmonary shunt, such as Glenn anastomosis and Fontan procedure can survive until adulthood recently and can be predicted to increasingly contribute to further numbers of IE [9].

4. Clinical findings

Pediatric IE presents non-specific symptoms and it creates a diagnostic challenge for clinicians and this is one of the reasons that high mortality of pediatric IE due to the failure to effectively- recognized it [10]. The most frequent symptoms and clinical signs are the same as IE without CHD, fever (>80%), malaise, fatigue, weight loss, arthralgia, headache, chills, and myalgia. Valvular lesions that produce leaflet destruction result in regurgitant murmurs, in contrast, the change of the heart murmur may not be recognizable in CHD with high-velocity jet flow shunting. Congestive heart failure occurs in up to half of the IE in CHD patients and is the leading cause of hemodynamic compromise due to the destruction of affected valves [9]. The frequency of cardiac episode-related complications in IE with CHD is equivalent to adults with structural heart disease [9]. In patients with cyanotic CHD and who have undergone systemic-pulmonary artery shunt, diminution of a continuous murmur and declining systemic oxygen saturation may reflect graft infection with obstruction of blood flow [2, 3, 4]. The endocarditis of patent ductus arteriosus or coarctation of the aorta can cause aneurysm formation and may rupture [21].

Even though Roth’s spots, Janeway lesions, Osler nodes, petechiae, Splinter hemorrhages, and splenomegaly are considerably less common in children compared to adults IE [2, 3, 4, 10], extracardiac episode-related complications of IE in CHD are frequent (up to 43%) and either caused by embolic events or immune phenomena [9]. Extracardiac manifestations of IE including emboli to the abdominal vessels, brain, and coronary arteries may produce severe symptoms associated with ischemia and/or hemorrhage [2]. Although systemic emboli by bacterial vegetation in the right heart rarely occurs because of filtration by the lungs [3], it can occur when the patient has right to left shunt such as cyanotic CHD (Figure 1) [21]. Although it is not frequent, pulmonary valve involvement can be seen more often in patients with in CHD than patients without CHD (Figure 2) [7]. Right-sided IE can cause chest pain, pulmonary infarction, pneumonitis, abscess, or asthma-like symptoms related to septic pulmonary embolization (Figure 3) [7, 21]. Chest X-ray shows infiltrative shadow when emboli to pulmonary arterial branches, and lung perfusion scintigraphy can indicate the lack of blood perfusion of this area (Figure 4) helps to differentiate from simple pneumonia.

Figure 1.

Brain CT findings of brain emboli by bacterial vegetation in the right heart in a patient with right to left shunt (a, b). Vegetations were detected on the tricuspid valve of a patient with unrepaired single ventricle physiology and many bacterial emboli in the lung were detected by chest CT at the same time (c, d).

Figure 2.

Transthoracic short axis echocardiogram in a patient with ventricular septal defect and two chambered right ventricle. Bacterial vegetation adhered to pulmonary valve (white triangle). Ao: Aorta, MPA: main pulmonary artery, PAV: pulmonary arteria valve, RVOT: right ventricle outlet tract.

Figure 3.

Septic pulmonary embolization and pneumonitis in a patient with unrepaired ventricular septal defect. Original bacterial vegetation was detected on the pulmonary valve. It disappeared when the patient complained of severe chest pain and chest X-ray finding showed infiltration.

Figure 4.

Emboli to pulmonary arterial branches in a patient with Truncus arteriosus repaired by Rastelli procedure. Chest X-ray showed infiltrative shadow (a) and lung perfusion scintigraphy indicated the luck of blood perfusion of this area (b). The photo of 2 years before showed no lack of perfusion in the same area (c).

Considering the results from many reports, vegetation size and location have a strong influence on the extracardiac episode-related complications and mortality [11, 26, 27, 28]. A vegetation size of ≥10 mm for left-sided IE and 20 mm for right-sided IE in adult patients is associated with a higher mortality [27, 28, 29, 30]. Especially for infants or small children, it seems to be more suitable to take into vegetation size relative to patient body size [11, 28]. Vegetation size adjusted for body surface area was a significant independent predictor of early mortality and overall mortality for left-sided IE in children and absolute vegetation size was not correlated with any adverse events [11]. The relative risk of operative mortality increased by 7% for every 1 mm/m² increase in vegetation size, and the absolute risk of operative mortality increased by 1.1% [11].

5. Microbiology

Blood culture should be indicated for all patients with CHD and/or previous cardiac endocarditis when patients have fever of unexplained origin. It is important to obtain adequate volumes of blood from patients including children and infants. But it is difficult and unfeasible to obtain the large amounts which are recommended for adults. Lesser amounts are optimal [4], for example, 1 to 3 ml in infants and young children and 5 to 7 ml in older children [2]. Three blood cultures should be obtained separately from different venipuncture sites on the first day, and two more blood cultures are recommended if there is no growth by the second day of incubation [2, 4]. Three separate blood cultures from venipuncture sites can be undergone over a brief period and empiric therapy is started because therapy should not be delayed in patients with acute IE [2, 3, 4]. If all the blood culture is negative, antibiotics can be withheld for >48 hours until further blood cultures are obtained when the patients are not severely ill and are clinically stable without signs of altered mental status or hemodynamic compromise [4]. Taking a blood culture of arterial blood is not recommended because it is not more useful than venipuncture. It does not increase yield over venous blood cultures [4].

Most frequently isolated organisms in IE patients with CHD are Gram-positive cocci, including Viridans group streptococci (VGS: e.g., Streptococcus sanguis, S mitis group, S mutans), staphylococci (both S aureus and coagulase-negative staphylococci (CoNS)), β-hemolytic streptococci, and enterococci [2]. Among them, Viridans group streptococci (VGS) are generally the most frequently isolated organisms [4, 9]. Staphylococcus aureus is usually the second most common cause of IE but the increasing percentage of Staphylococcus aureus-related IE is pointed out [3] and is now the most common cause in some studies [11] and is the most common agent of rapidly progressive IE [4]. Coagulase-negative staphylococci (CoNS) is the third most common bacterial isolate [11] and is seen more commonly in patients with prosthetic valves compared to native valves [9, 11]. The difference in the frequency of CoNS infection in pediatric CHD between prosthetic valve IE and native valve IE is approximately three times [11]. And this relationship is in accord with reports of IE in adult CHD [31]. Enterococcal endocarditis is relatively less common in children than in adults. Less frequently, other organisms such as the HACEK group of organisms (HACEK: Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are implicated [2, 9].

In infants, IE caused by Streptococcal viridans is rare and most cases caused by CoNS, fungi, or Staphylococcus aureus [8, 20].

IE associated with implanted prosthetic material frequently is caused by Staphylococcus aureus or CoNS. These organisms often are implanted at the time of surgery, and infection manifests within 60 days after cardiac surgery, but CoNS infection may present as late as ≥1 year after surgery [3, 4].

Culture-negative IE is not neglectable problem for patients with CHD. The prevalence of culture-negative IE is 5–12% [2, 3, 9]. The most common cause of culture-negative IE is current/recent antibiotic therapy or infection caused by a fastidious organism that grows poorly in vitro [9, 21]. And withdrawing of antibiotics for >48 hours should be considered to obtain further blood cultures when the patients are not severely ill [4].

6. Diagnostic imaging

Echocardiography is mandatory on any patient with suspicious of IE. In most pediatric cases, transthoracic echocardiography (TTE) is adequate for initial examination [32] because high-quality images can generally be obtained compared to adults and TTE is more sensitive in the pediatric patients than in adult patients for detection of vegetation [2]. And in young children and infants, transesophageal echocardiography (TEE) can be difficult to be undergone without general anesthesia. TEE should be considered if transthoracic windows are poor with difficulty to gain the complete visualization of higher-risk structures because of a prominent lung artifact, prosthetic valve, or material that is positioned behind the sternum or other location not well-visualized by transthoracic images [2, 3, 4, 32]. TEE should be undergone without delay if the IE was highly suspected and abnormal findings were not detected by transthoracic echocardiography [32]. The absence of vegetations on echocardiography does not deny the presence of IE including the finding by TEE [2, 33]. There is a very important consideration in patients with both of repaired and unrepaired CHD, who can have vegetations located in areas not readily visible even though by TEE (e.g., Blalock-Taussig shunt) [2, 33]. And it is revealed that IE among the patients with CHD are less likely to have visible vegetations irrespective of whether TTE or TEE is used [21]. On the other hand, echogenic masses can represent a sterile thrombus, sterile prosthetic materials, or normal anatomic variation rather than an infected vegetation [2].

When diagnosing endomyocardial damage using echocardiography is challenging especially in patients with prosthetic materials, cardiac computed tomography (CT) is a significant alternative method for diagnosis of IE [34]. Cardiac CT functions at a high specificity in IE of prosthetic valve and other prosthetic materials including shunts and conduits [35]. Cardiac CT is also useful to identify extra-cardiac features related to IE such as septic emboli (Figure 5) [36].

Figure 5.

Emboli of abdominal aorta by infective vegetation in a patient with tetralogy of Fallot with pulmonary atresia (white triangle). Poor blood circulation on the lower extremities was detected, and CT findings revealed obstructed descending aorta. Original fungal vegetation was located on the right atrium.

18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) is a molecular functional imaging technique and an emerging technology being used to diagnose endomyocardial damage. 18F-FDG PET/CT detects inflammation in the heart, especially around prosthetic materials and systemic inflammatory lesions caused by septic embolisms [10, 34, 37]. Although the diagnostic capability of 18F-FDG PET/CT is limited by low sensitivity in patients with native valve endocarditis probably due to its low sensitivity for detecting highly mobile small vegetations, 18F-FDG PET/CT is useful for diagnosing prosthetic valve endocarditis and perivalvular abscesses not only in left-sided IE but also in right-sided IE. Therefore, in patients with CHD and prosthetic materials and who are clinically suspected of IE, 18F-FDG PET/CT may be incorporated in the initial workup to increase the diagnostic sensitivity [34, 37].

7. Treatment

In general, the strategy of treatment of IE associated with CHD is comparable to that with IE not associated with CHD and antibiotic therapy is the mainstay of therapy. Guidelines for antibiotic therapy of IE have been published by the American Heart Association (AHA) and the European Society of Cardiology (ESC) [38, 39]. A prolonged course of therapy (at least 2 weeks and often 4 to 8 weeks) is necessary because infecting organisms are embedded within the fibrin-platelet matrix and exist in remarkably high concentrations with relatively low rates of bacterial metabolism and cell division, which results in decreased susceptibility of β-lactam and other cell wall-active antibiotics [2, 3, 9]. And cure of IE requires sterilizing vegetations [3, 9]. Bactericidal rather than bacteriostatic antibiotics must be administrated in high dosages whenever possible to decrease the possibility of treatment failures or relapses of IE [2, 3, 9]. Intravenous therapy is much preferable to oral to achieve higher serum antibiotics level. The course of antibiotic therapy varies based on the pathogen and the sites involved in the primary infection and any potential embolic sites [32]. Prosthetic material related IE and Staphylococcal IE are well known as complicated condition and recommended to be treated for longer period at least 4 to 6 weeks. Bacteremia generally resolves within several days after initiation of the appropriate antibiotics with enough dosages [2, 9]. 75% of patients become afebrile during first week and 95% during second week of appropriate antibiotic therapy. Work up to detect pathogen must be repeated when fever persists beyond this period, even though drug fever as a side effect of antibiotics must be considered [9]. Blood cultures should be performed at the end of the treatment and 4 weeks after completion of antibiotic therapy to check the relapse of infection [3, 9].

Fungal IE remains difficult to treat and mortality is up to 20 to 50% [3]. Even after combined intravenous antifungal management and surgical therapy, an on-going long-term antifungal therapy is often necessary to prevent a relapse of IE [9].

8. Surgery

Cardiac surgery is performed in approximately 16–20% of in IE patients with CHD [1, 9]. The three main indications of early surgery for IE are heart failure, prevention of embolic events and uncontrolled infection [39]. But the ideal timing for surgery is controversial subject in both of pediatric and adult IE related to CHD [9]. There is no indication of the surgical management only for IE in CHD patients and it is an extension of guideline for usual adult IE patients [4]. Surgery is considered for IE related to CHD with persistent bacteremia despite antimicrobial treatments, large mobile vegetations, prosthetic valves, prolonged clinical symptoms lasting more than 3 months, myocardial abscess formation with suspicions of atrioventricular block, mycotic aneurysms (Figure 6), previous IE, Staphylococcus aureus IE, left-sided IE, presence of systemic-to-pulmonary shunts, cyanotic CHD, and fungal IE [3, 4, 9]. The preventive operation for primary embolic events remains controversial because conflicting data on potential predictor of embolization were shown [26, 40]. Prediction of the embolic events remains difficult even in the adult IE [39]. An ‘embolic risk calculator’ were created to assess the embolic risk and evaluate the necessity of a surgery using six factors (age, diabetes, atrial fibrillation, previous embolism, vegetation length, and S. aureus infection) which associated with increased risk [41], but it is not suitable for pediatric patients. The highest risk of new embolism is seen during the first 2 weeks, especially first few days following initiation of antibiotic therapy and the risk rapidly decreases [42, 43]. For this reason, the benefit of surgery to prevent embolic events are greatest during the first 2 weeks of antibiotic therapy [39].

Figure 6.

A mycotic aneurysm in a patient with repaired tetralogy of Fallot (white triangle). A vegetation was detected on the mitral valve.

The overall operative mortality is reported as 5.8–15% in pediatric IE and 16.4% among adults [11, 12, 44]. Younger age, prosthetic valve IE, infection with Coagulase-negative staphylococci, increased duration of preoperative antibiotic therapy, shock, and the need for aortic valve replacement were all independently associated with mortality in multivariable analysis [11].

9. Prophylactic management

Medical procedures, including dental care, cardiac surgery, catheter interventions, and other non-cardiac invasive procedures are potential causes of bacteremia in up to 46%, 18%, 20%, and 20% of IE patients with CHD [9]. And IE can often be prevented by definitive repair of CHD or by reduction of bacteremia [3]. But in 2007, AHA revised the recommendation of antibiotics prophylactic guidelines to restrict preprocedural antibiotics to a few cardiac conditions that remain at higher risk for adverse outcomes related to IE [45]. And the guidelines on IE prophylaxis from international cardiology societies in 2008/2009 were greatly simplified and resulted in a drastic reduction in and limitation of cardiac diseases and procedures in which IE prophylaxis is indicated [46]. AHA guideline defines these specific cardiac conditions as follows: Prosthetic cardiac valve or prosthetic material used for cardiac valve repair, previous IE, unrepaired CHD with/without palliative shunts and conduits, completely repaired CHD with prosthetic material or device whether implanted by surgery or catheter intervention during first 6 months after the procedure, repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device [45]. And ESC guidelines recommended IE prophylaxis for the patients with untreated cyanotic CHD and those with CHD who have postoperative palliative shunts, conduits, or other prostheses. After surgical repair with no residual defects, the Task Force recommends prophylaxis for the first 6 months after the procedure until endothelialization of the prosthetic material has occurred [39]. But according to the study among pediatric cardiologists, more than half of the participants (56%) do not follow the current guidelines in certain conditions such as rheumatic heart disease, Fontan palliation without fenestration, and the Ross procedure [47]. There has never been a randomized, prospective study in patients with CHD to determine whether prophylactic antibiotics provide protection against.

IE during bacteremia-inducing procedures [3]. Given the prognosis, morbidity, and excessive cost of management of IE, appropriate prophylactic strategy for prevention of IE related to CHD should be established based on much more robust data and substantial evidence. And it is emphasized that good oral hygiene, prevention of oral disease, and skin hygiene are principal factor to prevent IE [3, 4, 32].

Conflict of interest

The authors declare no conflict of interest.