**7.1. Overall incidence of endocarditis in congenital heart disease**

Recently published research estimates the incidence of adult congenital heart disease (ACHD) associated IE is 1.0–1.33 cases per 1000 patient-years and in children (0–18 years), 0.41 cases per 1000 patient-years. Cumulative first incidence of IE, from birth to 18 years, was shown to be 6.1/1000 [5, 50, 51]. According to published data from the USA, the estimated incidence in children is lower, at 0.05–0.12 cases per 1000 patient-years [52, 53]. Interestingly, Marom et al. found 18% of children with IE had no underlying structural heart disease and no identifiable risk factors, compared to earlier published rates, ranging from 2.5–19% [54].

## **7.2. Incidence of endocarditis in complex congenital heart disease**

Incidence rate in complex CHD has recently been published by Kuijpers et al. [5], 2017. Incidence of IE (per 1000 patient-years) reported according to lesion-specific pathology include: pulmonary atresia (PA) with ventricular septal defect (VSD), 7.84; double outlet right ventricle (DORV), 3.59; Marfans, 2.35; univentricular heart (UVH), 1.9; Tetralogy of Fallot (ToF), 1.8; congenitally corrected transposition (cTGA), 0.93; transposition, 0.89; and Ebstein's anomaly, 0.7.

#### **7.3. Endocarditis in simple shunts**

#### *7.3.1. Ventricular septal defect*

Overall estimated incidence of IE with a VSD in ACHD is 1.0–1.33 and for children, 0.41 per 1000 patient-years (**Table 2**). In another study, the incidence was reported at 1.86 in adults and 1.06 in children, per 1000 patient-years (p = 0.06) [55]. The majority of studies have identified the following risk factors: i) unrepaired VSD ii) co-existent AR and, iii) residual defect at site of VSD repair. It has not been unequivocally proven a restrictive defect carries a higher risk. A VSD associated with AR carries a 2x relative risk (incidence increase from 1.25 up to 3.48/1000) [55], whilst a VSD that has undergone secondary aneurysmal transformation to form a Gerbode defect (LV-LA shunt) carries a risk of 5 per 1000 patient-years [56]. In one study, non-operated VSD's carried a 2.6x risk (0.73 versus 1.87/1000 patient-years) [55].

#### *7.3.2. Atrial septal defect*

**Overall incidence of IE in MVP (risk per 1000 patient-years)**

**6.3. Degenerative disease of the right-sided cardiac valves**

*6.2.2.2. Prevalence and risk of mitral prolapse in endocarditis*

24 Advanced Concepts in Endocarditis

Mitral valve prolapse occurs in 7–30% of cases of native valve IE, nearly always in the presence of MR and associated with redundant leaflets. Of note, NBTE forms on atrial aspect of thickened, redundant leaflets [17]. In a large clinicopathological correlation study of 120 native mitral valves excised due to IE, 43% had a history of prolapse [10]. The estimated risk of IE is shown in **Table 1**. Recent data published by Katan et al. [41] found a higher incidence of IE in MVP compared to earlier publications, thought in part due to the previous overestima-

Mitral regurgitation confirmed on echo and/or typical murmur, has been shown to be a predictor of risk in studies that have specifically assessed this variable (**Table 1**). In the study by Katan et al. [41], no cases of IE occurred in patients without a history of MR during follow-up. Nishimura et al. [47], found redundant leaflets (i.e. M-mode thickness ≥5 mm) were associated with IE, though numbers were small. Marks et al. [48] also confirmed classic MVP with leaflet thickening ≥5 mm (2-D echo) and redundancy was associated with IE risk over non classic MVP.

Gross degenerative changes of the right-sided valves are uncommon compared to the higherpressure environment of left-sided valves. The TV often undergoes only minimal change, with nodular thickening along the closing edge of the anterior valve leaflet. Mild diffuse leaflet thickening may occur in middle age; though in a minority of patients (>65 years), may become moderate or severe [28]. Myxoid degeneration of TV leaflets occurs occasionally [49], with TV prolapse (TVP) and PMD occurring in about 4% of cases [37, 40] . The risk of IE in TVP is unknown.

The pulmonary valve (PV) remains translucent and thin in the vast majority. Nodular thickening (noduli Morgani) along the centre part of the closing margin occurs in <50% of subjects,

tion of true MVP in healthy individuals using less stringent diagnostic methods [41].

*6.2.2.3. Mitral prolapse—echocardiographic predictors of endocarditis risk*

Retchin et al. [44] 0.3 n/a n/a Hickey et al. [45] 0.14 n/a 5.3 Danchin et al. [46] n/a n/a 14.5

**Table 1.** Risk of infective endocarditis associated with mitral valve prolapse and regurgitation.

Katan et al. [41] 0.87 0.631

Clemens et al. [42] and Tay and Yip [43]

Less than moderate MR.

At least moderate MR.

Flail leaflet.

1

2

3

**MVP with regurgitation (risk per 1000 patient-years)**

> ; 2.92 ; 7.163

0.38 n/a 15.1

**Overall incidence of IE in MVP with murmur (risk odds ratio** 

**– 'OR')**

Secundum ASD IE incidence is estimated at 0.23 for children and 0.28–0.64/1000 patient-years in adults (**Table 2**). A higher than expected risk was likely due to concomitant valve disease or misdiagnosed primum defects [50]. Isolated ASD is rarely associated with infective endocarditis [57]. The risk in adults with atrioventricular septal defect (AVSD) is estimated at 0.89 per 1000 patient-years (**Table 2**).


*7.3.3. Ductus arteriosus*

*7.3.4. Echocardiography*

surgery, 1.9 years) [60].

**7.5. Congenital aortic stenosis**

The estimated risk of IE with patent ductus arteriosus (PDA) is 0.24 and 0.35 per 1000 patientyears in adults and children, respectively, whilst other data have shown for an unrepaired PDA, the IE risk is 0.35–1.4 per 1000 patient-years, in a mixed adult and paediatric cohort [12, 50]. According to one study, the risk of IE was only present <4 years of age, likely due to liga-

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Echo assessment of a VSD should include identification of vegetations or other IE complications, whether involving the defect, the valves or mural endocardium. Also, imaging must define shunt anatomy, efficacy of closure (where present), cardiac chamber size and function, pulmonary artery pressure and haemodynamics. Aneurysmal formation and Gerbode defect should be excluded. Echo is fundamental in the routine and peri-procedural assessment of ASD and other shunts. It is also important to note the presence or absence of an ASD (or other shunt) in valvular endocarditis. For example, an infected TV may be a source of paradoxical embolism. The direction of the regurgitant jet and shunt, along with the size and mobility of

Bicuspid aortic valve (BAV) is a common congenital abnormality and undergoes accelerated degenerative change and dystrophic calcification [17]. Only a minority develop 'pure' regurgitation. Prevalence of BAV is as high as 1–2% of the population, more common in men and a pre-existing lesion in approximately 20% of cases of IE [12]. The estimated hazard ratio (HR) for adults with a BAV, of acquiring IE up to middle age is 6.3 (CI, 3.0–13.4), with an incidence of approximately 2 per 1000 patient-years [5, 58]. According to Kiyota et al. [59], BAV carries a relative risk (RR) of 23.1 times that of a tricuspid aortic valve for acquiring IE. With aortic coarctation (AoC), the incidence of IE is <1 per 1000 patient years [12, 58]. At 25 years out, the cumulative incidence of IE in another study was 3.5% (563 pts. with median age at time of

Incidence of IE in congenital aortic stenosis is estimated at 2.0–2.71 per 1000 patient-years [12, 61]. Echocardiographic predictors of risk of endocarditis include AV gradient and a nonstatistically significant increase in the presence of regurgitation. In the Second Natural History Study (NHS-2), Gersony et al. [55], found patients with peak gradient (PG) across the aortic valve of <50 mmHg had an IE rate of 0.45 per 1000 person-years versus 5.44 per 1000 personyears in those with gradient ≥50 mmHg. When the stenotic valve was associated with aortic regurgitation (AR), rates of IE increased from 1.98 up to 3.43 per 1000 patient-years (not statistically significant, p = 0.105) [55]. In those managed medically and with a PG < 50 mmHg, the

tion procedure essentially eliminating IE occurrence in older children [50].

a vegetation are important factors when assessing the risk of embolisation.

**7.4. Bicuspid aortic valve and aortic coarctation**

1 Left-sided includes: coarctation, aortic and mitral disease (Mylotte et al. and Rushani et al.); or LVOTO (left ventricular outflow tract obstruction), Marfan, BAV, CoA, MV defect, other LVOT (Kuijpers et al).

**2** Right-sided includes: Ebstein, anomaly of pulmonary artery/valve, TV disease (Mylotte et al. and Rushani et al); or Ebstein, RVOTO (right ventricular outflow tract obstruction), other (Kuijpers et al).

3 Cyanotic (complex/conotruncal) includes: PA + VSD, DORV, UVH, ToF, TGA, Other (Kuijpers et al).

**4** Cyanotic (conotruncal/single-ventricle): ToF, TGA, truncus, hypoplastic left heart and univentricular heart (Mylotte et al. and Rushani et al.)

5 Odds ratio when referenced to ASD, PDA, R-sided groups.

**Table 2.** Contemporary estimates of incidence and risk hazard ratios for infective endocarditis in children and adults with congenital heart disease, across selected lesion-specific groups.

#### *7.3.3. Ductus arteriosus*

**CHD ASD; VSD; AVSD; PDA**

1.33 0.64; 0.82; 0.89; 0.0

n/a n/a n/a n/a n/a

1.0 0.28; 0.65; n/a; 0.24

n/a n/a;

0.41 0.23; 0.24; n/a; 0.35

n/a n/a;

0.97 (0.56–1.66); n/a; 1.25 (0.5–3.13)

Left-sided includes: coarctation, aortic and mitral disease (Mylotte et al. and Rushani et al.); or LVOTO (left ventricular

Right-sided includes: Ebstein, anomaly of pulmonary artery/valve, TV disease (Mylotte et al. and Rushani et al); or

Cyanotic (conotruncal/single-ventricle): ToF, TGA, truncus, hypoplastic left heart and univentricular heart (Mylotte

**Table 2.** Contemporary estimates of incidence and risk hazard ratios for infective endocarditis in children and adults

2.81 (1.87–4.21); n/a; n/a

Incidence (per 1000 pt. years)

Adjusted HR (95% CI)

Incident IE (per 1000 pt. years)

Adjusted OR5, (95% CI)

Incidence (per 1000 pt. years)

Adjusted Rate Ratio (95% CI)

Odds ratio when referenced to ASD, PDA, R-sided groups.

with congenital heart disease, across selected lesion-specific groups.

outflow tract obstruction), Marfan, BAV, CoA, MV defect, other LVOT (Kuijpers et al).

Cyanotic (complex/conotruncal) includes: PA + VSD, DORV, UVH, ToF, TGA, Other (Kuijpers et al).

Ebstein, RVOTO (right ventricular outflow tract obstruction), other (Kuijpers et al).

Kuijpers et al. [5] (ACHD; Included prosthetic

26 Advanced Concepts in Endocarditis

Mylotte et al. [51] (ACHD; Excluded prosthetic valves; Included conduits

and repairs)

Rushani et al. [50], (Paediatric)

1

**2**

3

**4**

5

et al. and Rushani et al.)

valves)

**Left-sided1 Rightsided2**

1.89; 0.57

n/a n/a

1.61; 0.35

5.11 (3.6–7.25); n/a

0.44; 0.29

1.88 (1.01–3.49); 1.22 (0.52–2.86)

**Cyanotic (complex/conotruncal)3 Cyanotic (conotruncal/single** 

**ventricle)4**

1.94 n/a

n/a n/a

n/a 1.17

n/a

n/a 2.07

n/a

6.44 (3.95–10.5)

4.82 (3.12–7.46)

The estimated risk of IE with patent ductus arteriosus (PDA) is 0.24 and 0.35 per 1000 patientyears in adults and children, respectively, whilst other data have shown for an unrepaired PDA, the IE risk is 0.35–1.4 per 1000 patient-years, in a mixed adult and paediatric cohort [12, 50]. According to one study, the risk of IE was only present <4 years of age, likely due to ligation procedure essentially eliminating IE occurrence in older children [50].

## *7.3.4. Echocardiography*

Echo assessment of a VSD should include identification of vegetations or other IE complications, whether involving the defect, the valves or mural endocardium. Also, imaging must define shunt anatomy, efficacy of closure (where present), cardiac chamber size and function, pulmonary artery pressure and haemodynamics. Aneurysmal formation and Gerbode defect should be excluded. Echo is fundamental in the routine and peri-procedural assessment of ASD and other shunts. It is also important to note the presence or absence of an ASD (or other shunt) in valvular endocarditis. For example, an infected TV may be a source of paradoxical embolism. The direction of the regurgitant jet and shunt, along with the size and mobility of a vegetation are important factors when assessing the risk of embolisation.

#### **7.4. Bicuspid aortic valve and aortic coarctation**

Bicuspid aortic valve (BAV) is a common congenital abnormality and undergoes accelerated degenerative change and dystrophic calcification [17]. Only a minority develop 'pure' regurgitation. Prevalence of BAV is as high as 1–2% of the population, more common in men and a pre-existing lesion in approximately 20% of cases of IE [12]. The estimated hazard ratio (HR) for adults with a BAV, of acquiring IE up to middle age is 6.3 (CI, 3.0–13.4), with an incidence of approximately 2 per 1000 patient-years [5, 58]. According to Kiyota et al. [59], BAV carries a relative risk (RR) of 23.1 times that of a tricuspid aortic valve for acquiring IE. With aortic coarctation (AoC), the incidence of IE is <1 per 1000 patient years [12, 58]. At 25 years out, the cumulative incidence of IE in another study was 3.5% (563 pts. with median age at time of surgery, 1.9 years) [60].

#### **7.5. Congenital aortic stenosis**

Incidence of IE in congenital aortic stenosis is estimated at 2.0–2.71 per 1000 patient-years [12, 61]. Echocardiographic predictors of risk of endocarditis include AV gradient and a nonstatistically significant increase in the presence of regurgitation. In the Second Natural History Study (NHS-2), Gersony et al. [55], found patients with peak gradient (PG) across the aortic valve of <50 mmHg had an IE rate of 0.45 per 1000 person-years versus 5.44 per 1000 personyears in those with gradient ≥50 mmHg. When the stenotic valve was associated with aortic regurgitation (AR), rates of IE increased from 1.98 up to 3.43 per 1000 patient-years (not statistically significant, p = 0.105) [55]. In those managed medically and with a PG < 50 mmHg, the risk of IE was 0.27 per 1000 person-years and for patient with aortic valve replacement (AVR), follow-up rate of IE was 1.53 per 1000 person-years [55]. In a different study, the cumulative risk was 13.3% out to 25 years post-surgery (median age of surgery 7.0 years) in patients where follow-up was available. This equates to a higher annualised incidence of 7.2 per 1000 patient-years [60].

**8. Hypertrophic cardiomyopathy**

Hypertrophic cardiomyopathy (HCM) is an inherited genetic disorder characterised by myocardial thickening. Often this is asymmetric with marked involvement of the ventricular septum. In this setting, increased gradients are generated through the left ventricular outflow tract (LVOT) and if sufficient, result in systolic motion of the anterior mitral leaflet (SAM). Repeated trauma from contact between endocardial surfaces, results in formation of plaques on the ventricular septum, at the point of contact with the MV leaflet. There are altered mechanical and haemodynamic forces acting on the MV, AV and LVOT. This predisposes to endothelial trauma and inflammation, with the potential formation of NBTE and IE at multiple sites [17].

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Modern echocardiography is readily utilised to diagnose hypertrophic obstructive cardiomyopathy (HOCM). Typical criteria include an unexplained septal thickness of ≥15 mm and LVOT obstruction as a resting or provoked gradient of ≥30 mmHg. In one study [66], the incidence of IE was 1.4 per 1000 patient-years. Echocardiographic predictors of IE risk included: (i) resting LVOT obstruction with incidence of 3.0 per 1000 patient-years, and (ii) marked left atrial dilatation (in presence of resting LVOT obstruction) with incidence of 9.2 per 1000 patient-

There is overall conflicting data, with some studies finding IE is related to LVOT gradient and a propensity for MV infection, whilst other studies have found the contrary, with no particu-

The most common type of postinflammatory valve disease occurs as a sequela of rheumatic fever, leading to RHD. As discussed earlier in this chapter, the incidence has dramatically reduced in high-income countries, except in certain indigenous populations and remains a major global health burden across middle and low-income countries. In Australia, the estimated rate of ARF in young indigenous Australians aged 5–14 years is 150–380 per 100,000 person-years [68].

Rheumatic AV changes include thickening of the cusps, extending to the free margins and associated with commissural fusion. Calcification may eventually develop and occurs predominantly at the commissures and cusp margins. Concomitant changes at the MV are usual and involve thickening and retraction of the leaflets and chords along with commissural fusion. With 'pure' aortic regurgitation, there is cusp fibrosis with leaflet retraction. Fusion of the cusps may mimic a congenital BAV and a 'fish mouth' appearance of the MV on echo. Systemic lupus erythematosus and other inflammatory and autoimmune conditions can mimic rheumatic changes [16]. Rheumatic heart disease may involve all cardiac valves, but

years. Left ventricular wall thickness was not associated with increased risk [66].

**8.2. Echocardiographic diagnosis and predictors of endocarditis risk**

lar relation to LVOT gradient or predilection for AV or MV [67].

**9. Postinflammatory valve disease**

**9.1. Background and pathologic changes**

**8.1. Pathophysiology and diagnosis**

#### **7.6. Pulmonary valve and tetralogy of Fallot**

Pulmonary stenosis (PS) is usually related to congenital valve stenosis, sometimes in association with genetic syndromes. Pulmonary regurgitation (PR) due to congenital disease is mostly seen following previous repair of ToF or valvotomy [62]. Endocarditis of the PV is relatively uncommon both pre and post-surgery [55, 57, 60], except in palliative shunts [60]. In PS, a rate of 0.09 per 1000 person-years has been reported [55]. Tetralogy of Fallot carries a risk of approximately 1–2.3 per 1000 patient-years [12, 58].

#### **7.7. Post-surgical and catheter intervention**

In the Kuijpers et al. study [5], the following were noted: (i) 8 cases of IE with closed ASD, but of those, 6/8 were associated with a valve abnormality; (ii) 13 cases of IE with VSD, where 9/13 were open, and (iii) no cases of IE with PDA (83.6% were closed). A large population-based registry study of children who underwent surgical repair of congenital heart lesions reported no patient developed IE after surgical repair of PDA (620 patients, median age 2.6 years) and likewise in an ACHD population, no IE was reported [58]. The annualised risk of IE post repair of AoC has been estimated at 1.2 per 1000 patient-years [60]. Very uncommonly, early (<6 months) IE occurs after closure. Late onset IE is very rare and is usually due to delayed endothelialisation [63–65]. In fact, in a surgical follow-up study by Morris et al. [60], no children who underwent repair of an isolated secundum ASD developed IE following surgery. Small numbers were seen with primum ASD and complete AVSD. After 6 months post-surgical closure of ASD, VSD and PDA, the risk of IE is virtually eliminated. The same holds true for transcatheter closure, although with residual defects, the risk is not eliminated [52]. After definitive surgical repair of ToF, the risk is estimated at 0.7 per 1000 patient years but is much higher for a palliative shunt, at 8.2 per 1000 patient-years [60].

In a study by Rushani et al. [50], from the age of 0–6 months, unoperated cyanotic disease had an adjusted rate ratio (using ASD as a reference) for IE of 7.56, compared with the operated group at 9.22. For unoperated left-sided cardiac lesions, the rate ratio of IE was 2.35, though data was insufficient in the operated group to calculate the ratio [50].

In one study, the risk of IE was 5x increased early (<6 months) after any cardiac surgery in children [50] and 9.07x increased in adults up to 6 months after any non-valvular cardiac surgery [51]. Kuijpers et al. [5] reported valved-prosthetics in ACHD carry a hazard ratio (HR) of 17.29 (at 6 months), 15.91 (6-12 months) and 5.26 (>12 months) post-surgery. Non-valve containing prosthetics and repairs were associated with a HR of 3.34 at 0–6 months but no increase risk >6 months. The current European endocarditis prophylaxis guidelines (referred to elsewhere in this chapter) and US guidelines, accordingly recommend antibiotic prophylaxis for 6 months after complete closure of a defect with prosthetic material, regardless of whether it be percutaneously or surgically treated [57, 61].
