Definition

IE is an infection of the endothelium of the heart. Although the valves of the heart are most commonly affected, the infection can affect any endothelium-lined structures—including the great vessels, ductus arteriosus, or surgically placed shunts, patches, or prosthetics. Because bacteria are the primary microbial pathogens involved, the term bacterial endocarditis (BE) or subacute bacterial endocarditis (SBE) has been commonly used. However, a more inclusive term of infective endocarditis is preferred because it recognizes nonbacterial infections, such as those caused by fungus or virus. It should be noted that the term nonbacterial thrombotic endocarditis (NBTE) describes a spectrum of noninfectious lesions of the heart valves. Although this entity shares some features with IE, including echocardiographic appearance and risk for embolization, NBTE will not be discussed significantly in this chapter.

Epidemiology

IE is relatively uncommon, although incidence may be increasing over the last decade in adults and children. The increasing incidence of IE may be related to improved survival of patients with CHD and premature infants. Diagnostic value of echocardiography has improved, and advances in microbiologic techniques have led to improved isolation of microorganisms and reduced frequency of culture-negative IE.

Several large observational analyses have been recently published using national inpatient databases to evaluate the current incidence and risk factors of IE in the United States and Europe. A US database from 2000 to 2010 found an overall incidence of 0.43 per 100,000 children. IE accounts for anywhere between 0.5 and 4.6 out of 10,000 hospital admissions. Median length of stay for one series was 10 days.

A bimodal age distribution is noted in pediatric IE, with peaks in infancy and late adolescence ; 15% to 46% of pediatric IE occurs in the first year of life. Although many studies demonstrate rates of endocarditis being generally on the rise from year to year, there is particular interest in determining the impact of recently updated guidelines for SBE prophylaxis on the incidence of IE. Three large pediatric database studies have suggested no important change in IE rates during a study period that compared rates before and after the update, whereas two adult studies have noted a significant increase in IE incidence during the same time period.

Before 1970, rheumatic heart disease (RHD) was the primary risk factor for IE in the United States, accounting for 30% to 50% of cases. Since then the incidence of RHD (and therefore RHD-associated IE) in resource-rich countries has declined dramatically. However, RHD is a significant contributor to cardiac morbidity and mortality worldwide, specifically as it relates to IE. In a registry study in low- and middle-income African and Asian countries an incidence of IE in RHD was noted to be 3.7 per 1000 patient-years.

In the current era, an underlying heart condition, specifically CHD, is a primary risk factor for IE, accounting for 34% to 68% of children with IE. The changing epidemiology of IE has been comprehensively reviewed in children.

Microorganisms

Although many different microorganisms have been reported to cause IE, the vast majority of cases are caused by Staphylococcus and Streptococcus species. The major causes of IE in four key pediatric series are summarized in Table 70.2 . In earlier studies, 32% to 43% of cases of pediatric IE are caused by viridans group streptococci (VGS), which are common commensals of the oral mucosa consisting of several species, including Streptococcus mitis, Streptococcus sanguis , Streptococcus anginosus, Streptococcus salivarius , and Streptococcus mutans. In a recent large, national database study ( n = 1588 admissions) a causative microorganism was found in 632 admissions. S. aureus was the most commonly isolated microorganism (57%), followed by the VGS (20%) and coagulase-negative staphylococcus (CONS) in 14%.

IE due to VGS remains a primary cause of native valve IE in children with congenital or valvular heart disease without prior surgery. S. aureus and CONS are notable causes of acute IE following cardiac surgery (typically <60 days) and in the presence of prosthetic valves, endovascular materials, or indwelling vascular catheters. Both native and prosthetic valves can be infected by S. aureus . CONS are ubiquitous skin commensals that colonize CVCs and prosthetic devices, produce biofilms and abscess, and acquire multiantibiotic resistance. IE due to Enterococcus species is less common in children than in adults and is characterized by a subacute presentation typically affecting native valves or occurring in patients more than 60 days after cardiac surgery. The emergence of methicillin-resistant S. aureus (MRSA) strains and increasing resistance in Enterococcus faecium is a major concern.

Although catheter-related bacteremia due to gram-negative organisms such as enteric bacilli and Pseudomonas aeruginosa occurs frequently in hospital settings, these organisms are relatively uncommon as a cause of IE, likely due to their poor ability to adhere to endothelium. A wide variety of fastidious bacteria, zoonotic bacteria, and fungi may rarely cause IE. Infection caused by a fastidious group of gram-negative bacilli requiring special media for growth are the so-called HACEK organisms ( Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis , Eikenella corrodens , and Kingella spp.). HACEK are constituents of normal human oropharyngeal flora and remain susceptible to β-lactam agents. Fungal IE due to Candida or Aspergillus is unusual but may occur in neonates receiving parenteral nutrition with high glucose concentrations or immunocompromised children or following cardiac surgery, often involving prosthetic valves.

Approximately 5% of IE patients have negative blood cultures, but recent studies have reported culture-negative endocarditis (CNE) in 8% to 36% of IE cases. Negative blood cultures in IE patients may result from (1) previous administration of antimicrobial therapy; (2) infection due to fastidious bacteria, such as HACEK; (3) inadequate microbiologic methods; (4) fungal IE; and (5) right-sided endocarditis. CNE may be rarely caused by zoonotic pathogens such as Coxiella burnetii and Brucella (from livestock), Chlamydia psittaci (from parrots and pigeons), and Bartonella henselae (from cats).

Pathogenesis

Dating back to the 1970s, animal models have revealed a predictable pattern for the way that a pathogen can create IE in a host. First, there should be predisposing structural damage to the endocardium, either from congenital or acquired heart disease or indwelling CVC. The damaged endocardium activates the coagulation system to generate a local thrombus, consisting of fibrin, platelets, and red blood cells (RBCs). This thrombus serves as a nidus for circulating bacteria or fungus in the bloodstream to adhere to the endocardial surface. Finally, the pathogen must be able to propagate, grow, and lead to inflammatory and/or embolic sequelae.

The smooth endothelium of the heart and its valves is denuded primarily by mechanical stress from turbulent blood flow or direct trauma. Several cardiac lesions can create turbulent blood flow, including stenotic or regurgitant valves, shunt lesions, or abnormalities of the great vessels, like coarctation of the aorta. Endothelial damage typically occurs on the low-pressure side of a pressure gradient (e.g., the ventricular side of regurgitant semilunar valves, the atrial side of regurgitant atrioventricular valves, or the free wall of the right ventricle affected by a jet from a VSD). The integrity of the endothelium can also be interrupted by CVCs, pacemaker leads, and cardiac surgery.

Damaged endothelium induces thrombogenesis via local activation of the coagulation system. Platelets and fibrin adhere to injured endocardium and create a meshwork that may also involve leukocytes and RBCs. This sterile lesion is known as nonbacterial thrombotic endocarditis (NBTE). It can less commonly result from inflammation, rather than direct tissue injury. Thus even in the absence of direct endothelial damage, NBTE may develop in individuals with malignancies, burns, and systemic lupus erythematosus.

NBTE forms a nidus for infection by bacteria or fungus that may be present in the bloodstream. Activities of daily living (chewing, brushing, and flossing) incite transient bacteremia from oral flora. Noncardiac infections such as pneumonia or skin abscess can lead to bacteremia. Transient bacteremia is also noted when invasive procedures (like dental or genitourinary surgery, or the percutaneous introduction of a CVC) disrupt the integrity of mucosal surfaces that contain a dense microflora. When NBTE is caused by direct tissue damage from a CVC or pacemaker leads in the right ventricle, the nidus is typically right sided and prone to infection by introduction of pathogens through a percutaneous puncture site or through infected material passing through the catheter lumen itself. Right-sided endocarditis can alternatively be the result of intravenous drug use with contaminated needles.

Advances in molecular biologic techniques have resulted in greater understanding of virulence factors (adhesins) and complex host-pathogen interactions. Certain bacteria are more likely to adhere to NBTE and cause IE. The key pathogens for IE (VGS, S. aureus, and Enterococcus species) have a larger number of adhesins than other bacteria. These adhesins, known collectively as Microbial Surface Component Reacting with Adhesive Matrix Molecules (MSCRAMMs) mediate adherence to host proteins such as fibrin, fibronectin, and platelet proteins—whether they are part of NBTE or coating medical devices like pacemaker leads in the heart. Examples include clumping factor A and B, fibronectin-binding protein A and B, and Sdr (serine-aspartate repeat) protein from S. aureus and glucosyltransferases (GTFs), expressed by strains of VGS. In the case of clumping factor and GTF, an increased production of proinflammatory interleukins was noted when strains with these particular adhesins were involved. Animal models of streptococcal IE suggest dextran as another important virulence factor.

Biofilm production further facilitates bacterial persistence and contributes to antimicrobial tolerance. Adhesion leads to the formation of an infective vegetation, which further provokes the coagulation cascade and inflammatory response. Thus the vegetation grows and engulfs the pathogen—providing an environment in which it can replicate and escape from host defenses. In VGS an organized mass of fibrin encases a proliferating pathogen and substantially limits the ability of the host’s phagocytes or antimicrobial agents to penetrate it.

A growing infective vegetation can lead to local cardiac effects and systemic complications. Valve dysfunction can result from the mass effect of a primary vegetation or the destructive effects that a vegetation can have on a valve—namely loss of structural integrity, perforation of a valve leaflet, or aneurysmal changes leading to valvular regurgitation, and progression to heart failure in severe cases. Vegetations may less commonly obstruct inflow at the valve level, leading to valvar stenosis. IE can also spread locally within the heart—potentially invading the valve annulus, leading to an abscess, and/or into the myocardium. Alterations in heart function and cardiac conduction can be noted.

The systemic complications of IE result from (1) metastatic infection, due to persistent bacteremia or fungemia; (2) embolization of vegetations or pieces thereof; and (3) immune stimulation and antigen-antibody complex formation. Metastatic infection can occur in any organ, but the brain, lung, kidney, spleen, bone, joint, skin, or eye are most often affected. These secondary foci may undergo suppuration and may present as focal infections. Septic emboli can also lead to ischemia in the brain and lung, and less commonly to other organs. Hemorrhage may result from rupture of a mycotic aneurysm, from septic arteritis without mycotic aneurysm formation, or as a complication of infarction. Pulmonary emboli can lead to pneumonia, lung abscess, empyema, and infarction. Risk factors for embolization in pediatric IE include large vegetation (>10 mm), failure of vegetation to get smaller with appropriate antibiotics, and right-sided lesions.

In cases in which the infection lasts weeks to months (i.e., a subacute presentation), there is a heightened immune response that results in two primary clinical features. Splenomegaly in IE is thought to be caused by chronic reticuloendothelial hyperplasia. Glomerulonephritis (focal, segmental, or diffuse) due to the deposition of circulating immune complexes in the glomerular basement membrane often presents with hematuria.

Clinical Features

The clinical manifestations of IE are highly variable depending on the causative agent, the primary site of infection, and host factors. Typically, IE is primarily classified by the way in which it presents—acute versus subacute. Acute IE is generally characterized by a toxic-appearing patient, with high fevers, and, often, hemodynamic instability. S. aureus is the most common pathogen associated with acute IE and can cause rapid destruction of valve tissue, abscess formation, and embolic phenomena. More commonly, IE has a subacute presentation, often caused by VGS or CONS. Subacute IE presents with a slowly progressive course of some combination of nonspecific symptoms such as low-grade fever, anorexia, myalgia, arthralgia, or fatigue.

Clinical findings associated with IE are typically due to one of the four major components of the disease process: (1) direct cardiac manifestations, (2) embolic phenomena, (3) immune-complex disease, and (4) systemic manifestations of bacteremia or fungemia. Valve damage from IE typically results in valve regurgitation, which is manifested clinically by new or changing murmurs—diastolic murmurs with semilunar insufficiency and holosystolic murmurs for atrioventricular valve insufficiency. Cardiac auscultation may reveal a gallop rhythm, in addition to a myriad of other extracardiac findings (i.e., crackles or diminished breath sounds, hepatomegaly, or peripheral edema). When valve damage is severe, congestive heart failure develops and leads to complaints of exercise intolerance, dyspnea, or swelling. If IE affects a systemic-pulmonary shunt in cyanotic or single-ventricle CHD, then the obstruction from the vegetation may cause cyanosis and/or diminution of the associated murmur.

Embolic phenomena may result from right-sided or left-sided IE, and clinical manifestations vary according to the site affected. Right-sided IE can lead to pulmonary embolism, which may not be clinically relevant unless the emboli are large. Left-sided emboli can cause metastatic infection, ischemia, infarction, and/or hemorrhage. Hematogenous spread of infection can also lead to the formation of mycotic aneurysms. Although the kidneys can be affected by septic emboli, glomerulonephritis in IE is commonly the result of immune complex disease. Hematuria, proteinuria, and pyuria can be demonstrated on urinalysis, although impaired renal function is infrequent in children, compared with adults.

Several extracardiac manifestations of IE due to immune complexes and septic emboli have been classically described in adults but are relatively rare in children. Janeway lesions ( Fig. 70.1A ) are erythematous, macular, and tender lesions of the palms and soles that are due to septic emboli. Osler’s nodes (see Fig. 70.1B ) are raised, painful lesions on the pads of the fingers and toes and result from immune complex deposition. Roth spots (see Fig. 70.1C ) are retinal hemorrhages with white centers noted on funduscopy. They are mediated by immune complex disease and not specific for IE. Splinter hemorrhages (see Fig. 70.1D ) are seen to run vertically under the nails due to damage to small capillaries, likely from embolic phenomena.

Clinical manifestations of infective endocarditis. (A) Janeway lesion. (B) Osler’s node. (C) Roth spot (black arrow) along with cherry-red spot (white arrow) . (D) Splinter hemorrhage.

([A] from Beaulieu A, Rehman HU. Janeway lesions. CMAJ. 2010;182[10]:1075; [B] from Adams JG, Barton ED, Collings J, et al. Emergency Medicine: Clinical Essentials. 2nd ed. Philadelphia: Elsevier; 2013; [C] from Chang FP, Chien CY, Chaou CH, et al. Infective endocarditis with initial presentation of visual disturbances. Am J Emerg Med. 2016;34[10]:2052.e5-2052.e7; [D] from Chieng D, Janssen J, Benson S, et al. 18-FDG PET/CT scan in the diagnosis and follow-up of chronic Q fever aortic valve endocarditis. Heart Lung Circ. 2016;25[2]:e17-e20.)

Diagnosis

Diagnostic Criteria

With a variable presentation and no single test result that defines IE, specific diagnostic criteria were needed to facilitate research and epidemiologic efforts. These criteria are widely used in combination with good clinical acumen to make a clinical diagnosis. Published in 1994 by Durack and colleagues and modified by Li and colleagues in 2000, the Duke criteria provide a framework by which to evaluate a case based on clinical, pathologic, microbiologic, and echocardiographic findings ( Table 70.3 , Box 70.1 ). Although not specifically designed for use in children, these criteria have been validated in the pediatric population and have proven more sensitive than prior criteria.

TABLE 70.3

Definitions of Terminology Used in the Modified Duke Criteria

Major Criteria
Positive blood culture for infective endocarditis	Typical microorganism for infective endocarditis from two separate blood cultures
	• Viridans streptococci, a Streptococcus bovis, HACEK group, OR • Community-acquired Staphylococcus aureus or enterococci in the absence of a primary focus
	Persistently positive blood culture for microorganisms consistent with IE
	• At least two blood cultures drawn more than 12 hours apart, OR • All of three or a majority of four or more separate blood cultures—with first and last drawn at least 1 h apart • Single positive blood culture for Coxiella burnetii or anti–phase-1 IgG antibody titer >1 : 800
Evidence of endocardial involvement	Positive echocardiogram for infective endocarditis
	• Oscillating intracardiac mass, on valve or supporting structures, or in the path of regurgitant jets or on implanted material, in the absence of an alternative anatomic explanation, OR • Abscess, OR • New partial dehiscence of prosthetic valve • New valvular regurgitation (increase or change in preexisting murmur not sufficient)
Minor Criteria
Predisposition	Predisposing heart condition or IV drug use
Fever	≥38.0°C (100.4°F)
Vascular phenomena	Major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions
Immunologic phenomena	Glomerulonephritis, Osler’s nodes, Roth spots, rheumatoid factor
Microbiologic evidence	Positive blood culture but not meeting major criterion as noted previously b or serologic evidence of active infection with organism consistent with infective endocarditis

 

HACEK, Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella kingae; IgG, immunoglobulin G; IV, intravenous.

From Durack DT, Lukes AS, Bright DK, et al. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 96:200-209, 1994; and Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633-638.

a Including nutritional variant strains.

b Excluding single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

Box 70.1

Diagnosis of Infective Endocarditis Using the Modified Duke Criteria

Definite Infective Endocarditis

• 
  

  Pathologic criteria

  
  
  
  
  • 
    

    Microorganisms: demonstrated by culture OR

    
    
  • 
    

    Histologic evaluation in a vegetation OR

    
    
  • 
    

    In a vegetation that has embolized OR

    
    
  • 
    

    In an intracardiac abscess

    
    
  • 
    

    Pathologic lesions: Vegetation or intracardiac abscess—confirmed by histology showing active endocarditis

  
  
  
  
• 
  

  Clinical criteria, using specific definitions listed in Table 70.3

  
  
  
  
  • 
    

    Two major criteria OR

    
    
  • 
    

    One major and three minor criteria OR

    
    
  • 
    

    Five minor criteria

  
  

Possible Infective Endocarditis

• 
  

  One major criterion AND one minor criterion OR

  
  
• 
  

  Three minor criteria

Rejected

• 
  

  Firm alternate diagnosis for manifestations of endocarditis OR

  
  
• 
  

  Resolution of manifestations of endocarditis, with antibiotic therapy for 4 days OR

  
  
• 
  

  No pathologic evidence of infective endocarditis at surgery or autopsy, after antibiotic therapy for ≤4 days

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