**2. Epidemiology**

The incidence of IE is difficult to determine, because the diagnosis criteria and reporting methods vary with different series [2, 26]. The annual incidence of IE reported in Olmsted County, MN, was five to seven cases per 100,000 person-years, from 1970 to 2000, with practically no change in this period interval [27]. Parallel results of 1.7 per 100,000 person-years were reported from a survey in Louisiana [28], similar to reports from France (2.4/100,000 person-year) [19, 29] and United Kingdom [30]. But these results are less than incidence reports from the Delaware river Valley region (11.6/100,000 population) [31]. Several series have reported considerable increments in hospitalizations for IE, with most of the increase ascribable to *S. aureus* [32]. The proportion of acute cases of IE has increased from approximately 20% in the pre-antibiotic era, to more than 75% in the majority of high-income countries today [9].

When investigating at IE history, it can be seen that it affected children and young adults as a result of chronic rheumatic heart disease [33]; nevertheless, this remains the first key factor for IE in developing countries representing up to two-thirds of cases [34, 35] and infection is caused predominantly by community-acquired, penicillin-sensitive *Streptococci* entering via the oral cavity. The mean age of patients with IE has increased gradually in the antibiotic era. In 1926, the median age was younger than 30 years [36]; by 1943, it was 39 years [25], 50 years in the 1980s, and 55–60 years in the 1990s and 2000s [2, 12, 13, 19]. In a recent report including 58 centers in 25 countries, covering more than 2700 patients with definite IE by modified Duke criteria, the median age was 57.9 year [9]. In the period from 1993 to 2003, including 3784 patients with IE, the incidence of infection was <5 per 100,000 patients per year in individuals aged 50 years or less and >15 per 100,000 patients per year in those older than 65 years [12]. In a recent review comprising 3477 patients, the mean age of individuals with IE in 1980s was 45.3 years versus 57.2 years in 2000s [37]. These increasing rates of IE in the elderly could be the accumulation of factors such as improved living standards, which indirectly increase the population with degenerative valve disease hence leading to increasingly prosthetic valve surgeries in older patients. More men are affected than women; 58.6% in 1970s versus 66.3% in 2000s [37]. In a French study, the incidence of IE increased in patients older than 50 years and peaked at 194 infected per million habitants in men aged 75– 79 years (**Figure 1**) [10].

mortality and incidence are due to a continuing evolution of epidemiological features and risk factors rather to a lack of medical progress. The variability of disease presentation and course represents a challenge for the physician [8]. Even though clinical practices are clearly explained by international guides, they are derived mainly from observational cohort studies rather than randomized trials [17, 18]. Chronic rheumatic heart disease was considered a primary risk factor for IE until the widespread introduction of antibiotics; nevertheless, this finding prevails for low-income countries [14]. Current behavior in industrialized countries portraits different risk groups including prosthetic valve recipients, intravenous (IV) drug users, individuals with intravenous catheters, patients undergoing hemodialysis, and elderly people with degenerative valve lesions. Oral *Streptococci* are the main cause of IE in the general population [14, 19, 20], whereas *S. aureus* and coagulase-negative *Staphylococci* (e.g., *S. epidermidis*) are more frequently found in intravenous drug users, individuals with prosthetic-valve IE and in those with health-care-related IE [12, 21–23] and group *D Streptococci* (e.g. *S. gallolyticus*) are increasingly prevalent in elderly patients [12, 14, 19, 24, 25]. Patients with IE require opportune diagnosis and prompt response from a multidisciplinary group including cardiologists, cardiac surgeons, infectious disease specialists, and radiologists. The logistics of high-level patient care remains difficult even in developed countries and is frequently unobtainable in

The incidence of IE is difficult to determine, because the diagnosis criteria and reporting methods vary with different series [2, 26]. The annual incidence of IE reported in Olmsted County, MN, was five to seven cases per 100,000 person-years, from 1970 to 2000, with practically no change in this period interval [27]. Parallel results of 1.7 per 100,000 person-years were reported from a survey in Louisiana [28], similar to reports from France (2.4/100,000 person-year) [19, 29] and United Kingdom [30]. But these results are less than incidence reports from the Delaware river Valley region (11.6/100,000 population) [31]. Several series have reported considerable increments in hospitalizations for IE, with most of the increase ascribable to *S. aureus* [32]. The proportion of acute cases of IE has increased from approximately 20% in the pre-antibiotic era, to more than 75% in the majority of high-income countries today [9]. When investigating at IE history, it can be seen that it affected children and young adults as a result of chronic rheumatic heart disease [33]; nevertheless, this remains the first key factor for IE in developing countries representing up to two-thirds of cases [34, 35] and infection is caused predominantly by community-acquired, penicillin-sensitive *Streptococci* entering via the oral cavity. The mean age of patients with IE has increased gradually in the antibiotic era. In 1926, the median age was younger than 30 years [36]; by 1943, it was 39 years [25], 50 years in the 1980s, and 55–60 years in the 1990s and 2000s [2, 12, 13, 19]. In a recent report including 58 centers in 25 countries, covering more than 2700 patients with definite IE by modified Duke criteria, the median age was 57.9 year [9]. In the period from 1993 to 2003, including 3784 patients with IE, the incidence of infection was <5 per 100,000 patients per year in individuals aged 50 years or less and >15 per 100,000 patients per year in those older

low-income countries.

38 Contemporary Challenges in Endocarditis

**2. Epidemiology**

**Figure 1.** Incidence of infective endocarditis according to age and sex in a French population study of 497 patients. Zenith at 194 cases per million in men aged 75–79 years. Adapted from Selton-Suty et al. [10].

The causative agent has not changed much over time: *Staphylococci* spp., *Streptococci* spp., and *Enterococci* spp. still comprising more than 80% of all cases. Among these, *S. aureus* exceeds *Streptococci* spp. by 12% (**Figure 2**) [9].

**Figure 2.** Microbiologic etiology of endocarditis in 1558 patients. Fifty-eight hospitals in 25 countries between June 2000 and September 2005. Data from Murdoch DR, Corey CR, Hoen B., et al. [9]

#### **2.1. Health-care-associated endocarditis**

Owing to introduction of new therapeutic modalities (e.g., pacemakers, intravenous catheters, hyperalimentation lines, and dialysis shunts), health-care-associated IE, a relatively new form of the disease, has emerged [2, 9, 22, 23, 38–40]. Health-care-associated endocarditis includes nosocomial IE as well as community IE after a recent hospitalization or as a consequence of long-term indwelling devices. In a recent prospective, multinational cohort study from 61 hospitals in 28 countries comprising 1622 patients with native valve endocarditis (NVE), and no intravenous drug abuse, 34% of patients had health-care-associated endocarditis with nearly half being community acquired [40]. Infection may compromise normal valves, including the tricuspid valve, as well as implanted intracardiac devices and valves [9, 21, 40– 43]. The heart valve involved by infection varies considerably according to the different series. For mitral valve alone, the distribution ranges from 28 to 45%, aortic valve alone 5–36%, and aortic and mitral combined 0–35%. The tricuspid valve rarely is involved ranging from 0 to 6% and even less the pulmonary valve (<1%) [9, 44]. Health-care-associated IE accounts for 24 to 34% of cases not related to current cardiac surgery, and it involves an even larger proportion of cases in the United States [9, 23, 40]. Proportion of health-care-associated native valve endocarditis is 54% for nosocomial cases and 46% for community-based cases [40]. Mortality rates among these patients are high, ranging from 27 to 38%; aggravating factors include older patients and complex comorbidities [40, 41]. Among patients with health-care-associated IE, the largest subgroup belongs to individuals undergoing hemodialysis [22, 45]. Chronic hemodialysis has been identified as an independent risk factor for this type of IE [22, 40]. Patients undergoing hemodialysis have a higher risk of *S. aureus* infection causing IE [40, 45, 46]. The two most common pathogens related to health-care-associated IE are *Staphylococci* and *Enterococci*; the infection usually originates in the urinary tract or skin and intravenous lines or invasive procedures are often identified [40]. The risk of IE can be as high as 10% in cases of catheter-induced *S. aureus* bacteremia [39, 47, 48].

#### **2.2. Immunocompromised patient IE**

A special group is the immunocompromised patient who has a suboptimally functioning immune system. A number of conditions alter the immune response. The elderly has weak bactericidal response to infection. Impaired B-cell and T-cell function may develop in poor nutrition status or malnutrition. Hematologic and lymphoid malignancies and the medications used to treat them result in significant vulnerability to infection. The immune response is further reduced through the corticoids and cytotoxic drugs used to treat these conditions. Radiation therapy used to treat or palliate solid tumors and lymphoma suppresses antibody formation for weeks after treatment [49]. The degree of immunosuppression plays a major role in the outcome among human immunodeficiency virus (HIV)-infected patients with IE. Poor outcome is associated with a CD4+ cell count lower than 0.200 per 10(9)/L and left-sided or mixed IE [50, 51]. Common organisms associated with IE in HIV-infected patients are *S. aureus* and *Salmonella* [52]. Fungal microorganisms such as *Candida albicans, Aspergillus,* and *Crypto‐ coccus neoformans* are more common in IV drug abusers with HIV. These patients possess a greater risk of developing IE on the right-sided heart valves [52]. Infection with HIV should not preclude cardiac surgery.

#### **2.3. Prosthetic valve endocarditis.**

**2.1. Health-care-associated endocarditis**

40 Contemporary Challenges in Endocarditis

of catheter-induced *S. aureus* bacteremia [39, 47, 48].

**2.2. Immunocompromised patient IE**

Owing to introduction of new therapeutic modalities (e.g., pacemakers, intravenous catheters, hyperalimentation lines, and dialysis shunts), health-care-associated IE, a relatively new form of the disease, has emerged [2, 9, 22, 23, 38–40]. Health-care-associated endocarditis includes nosocomial IE as well as community IE after a recent hospitalization or as a consequence of long-term indwelling devices. In a recent prospective, multinational cohort study from 61 hospitals in 28 countries comprising 1622 patients with native valve endocarditis (NVE), and no intravenous drug abuse, 34% of patients had health-care-associated endocarditis with nearly half being community acquired [40]. Infection may compromise normal valves, including the tricuspid valve, as well as implanted intracardiac devices and valves [9, 21, 40– 43]. The heart valve involved by infection varies considerably according to the different series. For mitral valve alone, the distribution ranges from 28 to 45%, aortic valve alone 5–36%, and aortic and mitral combined 0–35%. The tricuspid valve rarely is involved ranging from 0 to 6% and even less the pulmonary valve (<1%) [9, 44]. Health-care-associated IE accounts for 24 to 34% of cases not related to current cardiac surgery, and it involves an even larger proportion of cases in the United States [9, 23, 40]. Proportion of health-care-associated native valve endocarditis is 54% for nosocomial cases and 46% for community-based cases [40]. Mortality rates among these patients are high, ranging from 27 to 38%; aggravating factors include older patients and complex comorbidities [40, 41]. Among patients with health-care-associated IE, the largest subgroup belongs to individuals undergoing hemodialysis [22, 45]. Chronic hemodialysis has been identified as an independent risk factor for this type of IE [22, 40]. Patients undergoing hemodialysis have a higher risk of *S. aureus* infection causing IE [40, 45, 46]. The two most common pathogens related to health-care-associated IE are *Staphylococci* and *Enterococci*; the infection usually originates in the urinary tract or skin and intravenous lines or invasive procedures are often identified [40]. The risk of IE can be as high as 10% in cases

A special group is the immunocompromised patient who has a suboptimally functioning immune system. A number of conditions alter the immune response. The elderly has weak bactericidal response to infection. Impaired B-cell and T-cell function may develop in poor nutrition status or malnutrition. Hematologic and lymphoid malignancies and the medications used to treat them result in significant vulnerability to infection. The immune response is further reduced through the corticoids and cytotoxic drugs used to treat these conditions. Radiation therapy used to treat or palliate solid tumors and lymphoma suppresses antibody formation for weeks after treatment [49]. The degree of immunosuppression plays a major role in the outcome among human immunodeficiency virus (HIV)-infected patients with IE. Poor outcome is associated with a CD4+ cell count lower than 0.200 per 10(9)/L and left-sided or mixed IE [50, 51]. Common organisms associated with IE in HIV-infected patients are *S. aureus* and *Salmonella* [52]. Fungal microorganisms such as *Candida albicans, Aspergillus,* and *Crypto‐ coccus neoformans* are more common in IV drug abusers with HIV. These patients possess a Different series suggest that prosthetic valve endocarditis (PVE) accounts for 10–30% of cases of IE in the developed world [23, 41, 53, 54]. In patients undergoing valve surgery between 1965 and 1995, the cumulative incidence of PVE ranged from 1.4 to 3.1% at 12 months and 3 to 5.7% at 5 years [42]. Associated risks for the development of PVE include male sex, previous native valve compromise, and long cardiopulmonary bypass for prosthetic valve placement [55]. Microbial seeding may occur in the early postimplantation period, before endothelialization has established. The incidence is greatest in the first 6 months after valve surgery, then declines to a lower but stable rate (0.2–0.35% per year) [56–58]. The range of age of PVE patients varies from 50 to 74 years [19, 43, 53, 59–62]. The risk of PVE is higher when valve replacement is performed during active IE, especially with unknown pathogen or incomplete antibiotic treatment [58, 63–66]. Mechanical prostheses seem to have a slightly higher risk for PVE in the first 3 months after implantation and bioprosthetic valves have a higher risk after 1 year of replacement [56, 64, 65], maybe as a result of degeneration of bioprosthetic leaflets. Although the cumulative risk comparing mechanical with biological prosthesis is similar [42, 67, 68], the weighted mean incidence for infections of bioprostheses calculated from different series is 0.49% per patient-year for mitral valves and 0.91% per patient-year for aortic valves. For mechanical prostheses, the incidence is 0.18% per patient-year for mitral, 0.27% per patientyearfor aortic, and 0.29% per patient-yearfor multiple implants [63]. PVE has been called *early* when infection occurred within 2 months of valve surgery and *late* when onset was >2 months. These terms were established to help distinguish PVE that instituted early as a complication of valve surgery from tardy infection that was likely to be community acquired [58, 69, 70]. However, in 2007, a study demonstrated a major shift according to the biological profile at 12 months after surgery, indicating that a more appropriate cutoff time to distinguish early from late PVE was 1 year [71]. Moreover, the European guidelines use this limit to classify the condition [17]. The causative pathogens involved in early PVE usually are methicillin-resistant *Staphylococci,* whereas in late PVE the common pathogens found are coagulase-negative *Staphylococci* and *Enterococci* (**Table 2**) [53]. In a large series including 2572 patients who underwent transcatheter aortic valve replacement (TAVR) in 14 centers between January 2008 and April 2013, the incidence of TAVR PVE was 1.13% (29 patients); the incidence of TAVR PVE by transfemoral approach was 1.1%, transapical 1.98%. The incidence of IE was 1.93% for balloon-expandable (23 of 1191) and 0.45% (6 of 1343) for self-expandable transcatheter heart valves. Early-onset IE (within 60 days) was diagnosed in 28% (eight patients), intermediateonset IE (between 60 and 265 days) was diagnosed in 52% (15 patients), and late-onset IE (>1 year) was diagnosed in 20% (six patients) resulting in 80% of incidence of IE within the first 12 months of implantation (higher rates), contrasting with surgical valve IE. In the early-onset group, *S. aureus* and coagulase-negative *Staphylococci* were the most prevalent (50%), in the intermediate-onset group *Staphylococcal, Enterococcal*, and *non‐viridans Streptococcal* species were the predominant pathogens (20% each), and in the late-onset group *Staphylococci* and *Enterococci* were identified(33% each), whichdoesnotresemble the late-onset surgicalPVE[72].


Adapted from Wang et al. [53]. \* Early refers to IE within 2 months and late after 2 months, according to Wang et al. HACEK: *Hemophilus, Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, Kingella kingae*. PVE: Prosthetic valve endocarditis.

**Table 2.** Causative organisms for early and late PVE.

#### **2.4. Cardiovascular-implantable electronic devices infection**

The most commonly used cardiovascular-implantable electronic device (CIED) are permanent pacemaker, cardiac resynchronization therapy, and implantable cardioverter-defibrillator. Most of these are implanted using transvenous leads. This practice had dramatically reduced the risk of infection associated with the procedure. Nevertheless, complication by infection remains a problem that can lead to significant morbidity, mortality, and elevated costs [73– 75]. Reports of CIED infection vary according to different series and range from 0.13 to 19.9% [76–78]. In a 16-year survey of Nationwide Inpatient Sample (NIS) from 1993 to 2008, the rate of CIED implantation increased 4.7% annually. The incidence of CIED infection remained stable until 2004, but increased almost twice in a 4-year period (2004–2008) from 1.53 to 2.41%, respectively [75]. The rate of infection associated with implantable cardioverter-defibrillator surpasses greatly that of the pacemaker [79–81].

#### **2.5. Ventricular-assist devices infection**

Patients who receive ventricular-assist devices (VADs) usually have various comorbidities, including a state of immune compromise. The risk of infection varies depending on the duration of VAD support [82]. Higher rates of infection are observed in the destination therapy group compared with the group where VAD is used as a bridge to transplantation [82]. Hravnak reported that registry patients with implant duration longer than 60 days were twice as likely to develop infection than those patients supported for less than 30 days [83]. The reported rates of infection in patients with VAD range from 13 to 80% and depend on multiple factors, including comorbidities, type of device implanted, and duration of VAD support [84]. Infection of VAD can present as three different syndromes: driveline infection (most frequent) presenting with local inflammatory changes and drainage at exit site, pocket site infection is the second syndrome presenting with local inflammatory changes, and the third (least frequent) is endocarditis comprising valves and/or internal lining of the device [84].

#### **2.6. Infection of closure devices (atrial septal defect, patent ductus arteriosus, and ventricular septal defect)**

Minimally invasive procedures are increasingly accepted as an option for cardiovascular congenital diseases [85–87]. Fortunately, complications derived from implantation of such devices are very rare, including infection (<1%) [85, 88–90].
