Epidemiology and pathophysiology of infective endocarditis

Introduction

The clinical features of infective endocarditis were first described in the 16th century by Jean François Fernel, a French physician who first introduced the term ‘physiology’ to describe the study of the function of living things [ ]. Over the next few centuries, through astute observations of human physiology and pathophysiology, several preeminent figures laid the foundations of our fundamental knowledge of infective endocarditis, including the pathogenesis of microorganisms, the formation of valvular lesions, and the clinical sequelae of embolization [ ]. In 1885, Sir William Osler, of the ‘Osler's node’ eponymous fame for this very disease, gave a series of landmark lectures that not only synthesized the large preceding body of knowledge into a coherent conceptual framework, but also brought endocarditis to the attention of the medical community [ ].

In the early 20th century, even as physician's understanding of endocarditis continued to evolve, morbidity and mortality remained high in the absence of effective treatments. Early regimens saw the use of sulfonamides, poisons such as mercury and arsenic, and hyperthermia, and cure rates were expectedly nonexistent [ , ]. Fortunately, the 20th century also saw parallel advances in the field of microbiology and biochemistry. The discovery of penicillin by Sir Alexander Fleming in 1928, and later the first successful clinical trials and refinement of mass production techniques by Howard Florey, Ernst Chain, and Norman Heatley in the 1940's finally provided physicians with hopes of a cure.

Penicillin drastically changed the natural course of the disease as it was highly effective against the wild-type Staphylococcus and Streptococcus bacterial strains that had not yet experienced artificial selective pressure. As this medical miracle saw use even beyond endocarditis, it was befitting that Sir Alexander Fleming, after having received the 1945 Nobel Prize in Physiology or Medicine for its discovery, forewarned the emergence of resistance [ ]. Indeed, within mere years after widespread use physicians began to see resistant Staphylococcus aureus among other resistant organisms, and thus began an evolutionary arms race that continues to this day [ ].

Penicillin also marked the beginning of an ever-changing landscape of infectious endocarditis. Medical advances through the rest of the 20th century and into the early 21st century include the development of novel antibiotics, use of cardiovascular implantable electronic devices (CIEDs) and prosthetic valves, the ubiquitous use of long-dwelling venous catheters, and a growing hemodialysis population—all of which have impacted clinical practice and management [ ]. In addition, the growing opioid epidemic in America has affected both the prevalence and incidence of right-sided endocarditis and introduced rare organisms into the microbiology [ , ]. Together, all these changes have influenced the epidemiology of endocarditis considerably.

General epidemiology

Infectious endocarditis remains a rare disease, with an incidence of 2–10 cases per 100,000 people, and varies according to world regions, country, and even different areas within a nation's borders [ ]. In countries with consistent reporting, the overall incidence appears to be at least stable, if not slightly increasing [ , ]. Despite these statistics, the epidemiology has changed significantly over the years. Infectious endocarditis in the preantibiotic era predominantly affected those in their 30 to 40s, often in the setting of rheumatic valvulopathy, and with Streptococcus spp. as the predominant pathogen [ , ]. However, beginning in the 20th century, as the nations of the world began to diverge in terms of industrialization and wealth, so too have the features of infective endocarditis between low- and high-income countries. Low-income countries continue to retain their preantibiotic era features, with rheumatic disease remaining a key risk factor, affecting up to two-thirds of cases [ ]. High-income countries, on the other hand, have seen rheumatic disease fall to the wayside in the setting of improved living conditions and readily available treatment for Streptococcus pharyngitis [ , ]. In its stead, it has been replaced by an older population, with a different set of risk factors, and a changing microorganism profile [ ].

The average age of infective endocarditis in high-income countries in the early 21st century has now risen to the 60 and 70s, with a relatively even split between genders [ , , , ]. This shift in age is a direct reflection of an increased life expectancy, with age-related comorbidities, and the procedures necessary for their management [ , , ]. General age-related risk factors include hypertension, diabetes, coronary artery disease, and kidney and liver disease [ , ]. Because of the increasing end-stage renal disease (ESRD) population, hemodialysis is now one of the biggest risk factors for infectious endocarditis, accounting upward of 25% of infective endocarditis cases surveyed [ , ]. Valvulopathies, both congenital such as bicuspid aortic valves, and age-related such as regurgitation and prolapse, also convey risk [ ]. The affected valves are predominantly left-sided, most commonly the aortic valve, with right-sided infective endocarditis being much rarer at around 5%–10% [ , ]. Unfortunately, repair of these various valvular diseases with prosthetic devices only serve to further increase the risk, accounting upward of 20% of cases [ , , , ]. Similarly, the rising prevalence of CIEDs for the treatment and management of various cardiovascular diseases has also been accompanied by a concomitant rise in device-related infective endocarditis [ , ].

The microbiology of infective endocarditis in high-income countries has also changed as a direct consequence of medical advancement. Prior to 1960 and 1970s, viridans group streptococci accounted for the majority of cases [ ]. However in the last few decades, staphylococcal species have now supplanted viridans streptococci, now accounting for up to 40% of cases, with S. aureus as the predominant organism [ , , , ]. This change in pattern is attributed to a growing immunocompromised population such as those on long-term steroids and other immunosuppressive medications, and those with solid organ or bone marrow transplants [ ]. This change also parallels a rise in the use of long-term dwelling catheters, increase in invasive procedures such as transcatheter aortic valve replacement (TAVR), and the ubiquity of prosthetic devices including prosthetic valves and CIEDs [ , , , ]. For similar reasons, there has also been an increase in Enterococcus spp., β-hemolytic Streptococcus spp., and nutritionally variant Streptococci [ , ]. The percentage makeup of rare organisms such as gram-negatives, fungus, and atypical bacteria remain low [ , , , ].

Infective endocarditis in injection drug users

Infective endocarditis in intravenous drug users comprises a unique epidemiologic group. The population is younger with a median age of 40, and affects more males (55%–58%) than females [ , , ]. The annual rate varies from 1.5 to 20 per 1000 users, representing a 20x higher rate of risk than the general population [ , ]. Cases have risen alongside the growing opioid epidemic, reaching upward of one-third of all infective endocarditis cases in certain tertiary care centers [ ]. In contrast to nonusers, infective endocarditis in injection drug users is predominantly right-sided (76%–79%), with a smaller proportion affecting left-sided valves (16%–30%) or involving both sides (5%–10%) [ ]. Of the affected right-sided valves, there is a preference for the tricuspid valve, upward of 69% [ , ]. This predilection for right-sided valves is believed to be due to direct injection of chemical substances and microorganisms into the venous system, causing both caustic and physical damage to the valvular tissue leading to subsequent infectious seeding [ , ]. There is also data to suggest that certain vasoactive drugs, particularly cocaine, may cause vascular vasospasm of the valvular intima, triggering local injury and thrombus formation to act as a nidus for infection [ ]. This mechanism may also explain why noninjection substance users have a higher risk of infective endocarditis [ ].

Similar to nonusers, S. aureus is the most common organism, but at a significantly much higher percentage, with one comparison study showing 68% in injection drug users compared to 28% in nonusers [ , ]. This stark difference is felt to be due to increased rates of S. aureus colonization [ , ]. Following Staphylococcus , Streptococci spp. and Enterococcu s spp. are the next most common pathogens [ ]. What was statistically ‘rare’ in the nonuser population were more common in the setting of injection drug use, with higher rates of gram-negatives such as Pseudomonas , fungal pathogens (especially Candida spp.), and polymicrobial infections [ , , ]. In addition, because of habits associated with injection drug use and associated paraphernalia such as oral preparation of the needle and of the injection site, HACEK organisms and other oral flora are also not uncommon [ ].

Morbidity and mortality

Infective endocarditis has substantial morbidity and mortality. Several factors influence the overall prognosis including the specific pathogen(s) involved, presence of embolic phenomenon and infectious complications, preexisting comorbidities, degree of valvular involvement, and necessity of surgical intervention [ ]. Depending on the clinical situation, initial in-hospital mortality can range anywhere from single-digits to as high as 45% [ , , ]. Poor prognostic factors include left-sided or paravalvular involvement, prosthetic valve endocarditis (PVE), presence of multiple comorbidities, CNS involvement, advanced age, and Staphylococcus or fungal infections [ , ]. Even with modern medicine, prognosis continues to remain poor, with 1-year mortality as high as 40% [ , , , ]. In one study using mathematical modeling, those with infective endocarditis continue to have lower survival rates compared to that expected of the general population at 1 year (90% infective endocarditis (IE) vs. 92% non-IE), 3 years (81% IE vs. 86% non-IE), and 5 years (70% IE vs. 82% non-IE), demonstrating that IE continues to convey excess morbidity and mortality for years after the initial diagnosis [ ].

Clinical outcomes for those with Intravenous drug use (IVDU) also have high morbidity and mortality. One comparison study between users and nonusers show comparable initial in-hospital mortality (6% IVDU vs. 9% non-IVDU, P > .05) and 1-year all-cause mortality (16% IVDU vs. 13% non-IVDU, P > .05) [ ]. Another comparison study showed that while IVDU had better survival in initial in-hospital mortality (6.8% IVDU vs. 9.6% non-IVDU, P < .001) and 30-day readmission mortality (3.4% IVDU vs. 7.9% non-IVDU, P < .001), mortality at later readmissions between 30 days and 180 days was similar (4% IVDU vs. 3.8% non-IVDU, P > .05) [ ]. Long-term prognosis for IVDU is similarly poor, with longitudinal studies showing overall mortality reaching as high as 30%–40% [ , ]. These comparable survival rates for IVDU, despite higher risk behavior, can be attributed to a younger population with fewer preexisting comorbidities [ ]. Another potential explanation is the higher rate of right-sided valvular involvement in those with IVDU, as right-sided infective endocarditis has more favorable outcomes [ ]. On the contrary, left-sided infective endocarditis in IVDU is worse than nonusers [ ].

Because of the poor prognosis, there is interest in identifying root causes to improve clinical outcomes. It is known that prompt diagnosis, appropriate antibiotic administration, and early evaluation for surgical candidacy are crucial to improve survival [ , ]. Unfortunately, this does not always occur, with reports of delayed diagnoses, inappropriate antibiotic use, delays in surgical interventions, or simply not following or deviating from expert guidelines [ , ]. As such, multiple expert groups now recommend establishing a multidisciplinary team for the management of infectious endocarditis given the complexity of the disease [ , , ]. These ‘endocarditis teams’ have been shown to reduce both in-hospital and long-term mortality, decrease complications from infectious embolic phenomenon, a reduction in time to appropriate surgical intervention, and lower surgical mortality [ , ]. In fact, endocarditis teams have shown to be independent positive predictors of 1-year survival [ ].

Introduction

The vascular endothelial lining has evolved to perform several vital functions including the regulation of vascular tone, exchange of molecules between blood and tissue compartments, immune system regulation, and homeostasis [ ]. Promotion of bacterial and fungal adhesion is absent from these functions. This is not an evolutionary omission but rather a protective mechanism. The bloodstream is considered a sterile body site [ ] but when microbes gain entry into this space, the endothelial lining functions as a protective barrier ( Fig. 1.1 ) .

In general, there are four critical factors that must be accomplished in successive order for the development and propagation of infective endocarditis. Those factors include the development of endothelial damage, pathogen access into the intravascular space, pathogen adherence to the endothelium, and pathogen proliferation [ ].

A variety of factors can lead to endothelial damage, including mechanical forces, autoantibodies, inflammatory injury, as well as direct insults from the pathogens themselves [ ]. The most important of these factors, pathogenic virulence will be discussed in further detail later in this book. Once the endothelial lining of the valve has suffered an insult, the next step of the process is merely a waiting game for a pathogen to gain entry into the bloodstream. Whether through mucosal breakage, hematogenous spread from another infected tissue, or direct inoculation of the bloodstream as in the case of intravenous drug use or an indwelling catheter, once an organism has entered the bloodstream, it has the potential to adhere to the damaged valve and initiate pathogenesis.

Pathogens can directly adhere to the damaged lining or they can adhere to a sterile platelet-fibrin thrombus, acting as an infectious nidus [ ]. Pathogens have varying affinity for adherence to the endothelial lining. S. aureus , for instance, has a very high affinity for adhesion, whereas most Enterobacterales (formerly known as Enterobacteriaceae) have a much lower affinity for adhesion. S. aureus is also unique in that it has the ability to directly infect intact endothelium, which contributes to its overall high rate of infectivity [ ].

With the pathogen attached to the valve, ongoing replication then allows for the development of vegetation, or a proliferative infectious mass. Individual pathogen virulence factors and the host immune system play vital roles in this process by promoting ongoing replication and survival [ ].

Overview of pathogens

A thorough understanding of the patient in front of you will often permit the clinician to predict the causative organism with relative degree of accuracy. There is a direct correlation between a patient's exposure history and the patient's microbiologic etiology of an infection. This association is quite strong with infective endocarditis. Gram-positive cocci including Staphylococcus spp. (skin), Streptococcus spp. (skin, mouth, gastrointestinal (GI) tract), and enterococci (GI and genitourinary (GU) tracts) each compromise a unique niche of normal human flora. Breaks in the skin and/or mucosal surfaces promote hematogenous inoculation. Once access to the bloodstream has been obtained, these organisms, to varying degrees, exhibit enhanced binding to damaged vasculature which increases their propensity to infect heart tissues. Conversely, gram-negative rods primarily colonize the respiratory, GI, and GU tracts and demonstrate decreased abilities to stick to cardiac tissue. However, disruptions of the GI and GU tracts can permit hematogenous dissemination of gram-negative rods (GNRs) with varying degrees of risk for infective endocarditis, depending on underlying patient- and pathogen-specific factors. The third important group of pathogens to be considered is yeast, specifically Candida spp. These fungi often colonize the GI tract and plan an important role in both nosocomial and PVE. More detail on the various pathogens associated with infective endocarditis will be explained in a subsequent chapter.

The microbe's role in vegetation

As vegetation matures, it becomes a meshwork of fibrin, platelets, white and red blood cells, and interspersed conglomerates of bacteria. The vegetation develops into a complex ecosystem that functions to protect the bacterial organisms from the innate immune system as well as antimicrobials. Outer layers of fibrin function as a defense against phagocytic cell penetration. Bacteria deep within the vegetation experience reduced targeting from the immune system and exist in reduced metabolic states, which can provide added protection against antimicrobials which target rapidly dividing and metabolically active bacteria (i.e., beta-lactams) [ ]. The fibrin/cellular matrix can persist long after the infectious component of the vegetation has been eradicated, and in the absence of surgical extraction of the vegetation, it can take months or even years for the immune system to clear out the dead bacteria and microorganism debris from the vegetation [ ].