Infective endocarditis (IE) is defined as an infection of the endocardial surface of the heart, which may

include one or more heart valves, the mural endocardium, or a septal defect. Its intracardiac effects
include severe valvular insufficiency, which may lead to intractable congestive heart failure
and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through
several mechanisms, including both sterile and infected emboli and various immunological phenomena.
The history of IE can be divided into several eras. Lazaire Riviere first described gross autopsy findings of
the disease in 1723. In 1885, William Osler presented the first comprehensive description of endocarditis
in English. Lerner and Weinstein presented a thorough discussion of this disease in modern times in their
landmark series of articles, Infective Endocarditis in the Antibiotic Era, published in 1966 in the New
England Journal of Medicine.
IE currently can be described as infective endocarditis in the era of intravascular devices, as infection of
intravascular lines has been determined to be the primary risk factor for Staphylococcus
aureus bloodstream infections (BSIs). S aureus has become the primary pathogen of endocarditis.
IE generally occurs as a consequence of nonbacterial thrombotic endocarditis, which results from
turbulence or trauma to the endothelial surface of the heart. A transient bacteremia then seeds the sterile
platelet/fibrin thrombus, with IE as the end result. Pathologic effects due to infection can include local
tissue destruction and embolic phenomena. In addition, secondary autoimmune effects, such as immune
complex glomerulonephritis and vasculitis, can occur. (See Pathophysiology.)
IE remains a diagnostic and therapeutic challenge. Its manifestations may be muted by the indiscriminate
use of antimicrobial agents or by underlying conditions in frail and elderly individuals or
immunosuppressed persons. (See Diagnosis.)
Effective therapy has become progressively more difficult to achieve because of the proliferation of
implanted biomechanical devices and the rise in the number of resistant organisms. Antibiotic prophylaxis
has probably had little effect in decreasing the incidence of IE. (See Treatment and Management.)
For other discussions on IE, see Pediatric Bacterial Endocarditis, Infectious Endocarditis, Neurological
Sequelae of Infective Endocarditis, and Antibiotic Prophylactic Regimens for Endocarditis.

Types of infective endocarditis

Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must
not be misdiagnosed or overlooked. Endocarditis can be broken down into the following categories:

Native valve endocarditis (NVE), acute and subacute

Prosthetic valve endocarditis (PVE),[8] early and late
Intravenous drug abuse (IVDA) endocarditis
Other terms commonly used to classify types of IE include pacemaker IE and nosocomial IE (NIE).
The classic clinical presentation and clinical course of IE has been characterized as either acute or
subacute. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the
distinction between these 2 major types; however, the classification still has clinical merit. [9]
Acute NVE frequently involves normal valves and usually has an aggressive course. It is a rapidly
progressive illness in persons who are healthy or debilitated. Virulent organisms, such as S aureus and
group B streptococci, are typically the causative agents of this type of endocarditis. Underlying structural
valve disease may not be present.
Subacute NVE typically affects only abnormal valves. Its course, even in untreated patients, is usually
more indolent than that of the acute form and may extend over many months. Alpha-hemolytic
streptococci or enterococci, usually in the setting of underlying structural valve disease, typically are the
causative agents of this type of endocarditis.

PVE accounts for 10-20% of cases of IE. Eventually, 5% of mechanical and bioprosthetic valves become
infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and,
after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are
more susceptible than those in the aortic areas.[8]
Early PVE occurs within 60 days of valve implantation. Traditionally, coagulase-negative staphylococci,
gram-negative bacilli, and Candida species have been the common infecting organisms. Late PVE occurs
60 days or more after valve implantation. Staphylococci, alpha-hemolytic streptococci, and enterococci
are the common causative organisms. Recent data suggest that S aureus may now be the most common
infecting organism in both early and late PVE.[10]
In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections
involve the tricuspid valve.[11] S aureus is the most common causative organism.
Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these
devices are infected within a few months of implantation. Infection of pacemakers includes that of the
generator pocket (the most common), infection of the proximal leads, and infection of the portions of the
leads in direct contact with the endocardium.
This last category represents true pacemaker IE, is the least common infectious complication of
pacemakers (0.5% of implanted pacemakers), and is the most challenging to treat. Of pacemaker
infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive.
NIE is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated
with a hospital, based on a procedure performed within 4 weeks of clinical disease onset. The term
healthcare-associated infective endocarditis (HCIE) is preferable to NIE, since it is inclusive of all sites
that deliver patient care, such as hemodialysis centers. The term NIE should be applied to cases of IE
acquired in the hospital. An appropriate alternative term would be iatrogenic IE.
Two types of NIE have been described. The right-sided variety affects a valve that has been injured by
placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a
nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to
occur on the left side.S aureus has been the predominant pathogen of NIE/HCIE since the recent
prevalence of intravascular devices. Enterococci are second most commonly isolated pathogens. These
usually arise from a genitourinary source.

Evolution of clinical characteristics of infective endocarditis

Since the 1960s, the clinical characteristics of IE have changed significantly. The dramatic graying of the
disease and the increase in recreational drug use and proliferation of invasive vascular procedures
underlie this phenomenon. Varieties of IE that were uncommon in the early antibiotic era have become
prominent. Cases of NIE, IVDA IE, and PVE have markedly increased. Valvular infections have entered
the era of IE caused by intravascular devices and procedures.
The underlying valvular pathology has also changed. Rheumatic heart disease currently accounts for less
than 20% of cases, and 6% of patients with rheumatic heart disease eventually develop IE. Approximately
50% of elderly patients have calcific aortic stenosis as the underlying pathology. Congenital heart disease
accounts for 15% of cases, with the bicuspid aortic valve being the most common example.
Other contributing congenital abnormalities include ventricular septal defects,patent ductus arteriosus,
and tetralogy of Fallot. Atrial septal defect (secundum variety) is rarely associated with IE. Mitral valve
prolapse is the most common predisposing condition found in young adults and is the predisposing
condition in 30% of cases of NVE in this age group. IE complicates 5% of cases of asymmetrical septal
hypertrophy, usually involving the mitral valve.

PATHOPHYSIOLOGY
IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the
aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve.
Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.
All cases of IE develop from a commonly shared process, as follows:
1. Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valve
2. Adherence of the organisms
3. Eventual invasion of the valvular leaflets
The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile
fibrin-platelet vegetation. The development of subacute IE depends on a bacterial inoculum sufficient to
allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced
by agglutinating antibodies.
In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma
from intravenous catheters or pacing wires (ie, NIE/HCIE). S aureus can invade the endothelial cells
(endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the
cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure,
malnutrition, systemic lupus erythematosus, or neoplasia.
The Venturi effect also contributes to the development and location of nonbacterial thrombotic
endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the
sides of the low-pressure sink that lies just beyond a narrowing or stenosis.
In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial
surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these
examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect,
the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect.
Nonbacterial thrombotic endocarditis may also form on the endocardium of the right ventricle, opposite
the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum
patch).
The microorganisms that most commonly produce endocarditis (ie, S aureus; Streptococcus
viridans; group A, C, and G streptococci; enterococci) resist the bactericidal action of complement and
possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other
characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the
following:

Increased adherence to aortic valve leaflet disks by enterococci, S viridans,and S aureus

Mucoid-producing strains of S aureus
Dextran-producing strains of S viridans
S viridans and enterococci that possess FimA surface adhesin
Platelet aggregation by S aureus and S viridans and resistance of S aureusto platelet microbicidal
proteins
The pathogenesis of pacemaker IE is similar. Shortly after implantation, the development of a fibrinplatelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the
generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding
the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection
during a bacteremia.

Bacteremia (either spontaneous or due to an invasive procedure) infects the sterile fibrin-platelet
vegetation described above. BSIs develop from various extracardiac types of infection, such as
pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade
gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of
subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg,
brushing teeth, bowel movements).
The skin is quite resistant to S aureus infection due in great part to its production of antimicrobial
peptides. Soong et al discovered that, in vitro, the secretion of alpha toxin by S aureus allows the
organism to successfully penetrate the keratinocyte layer. This could explain the presence of
staphylococcal bacteremia in the absence of any gross damage to the epithelial layer. [12]
Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of
esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive
procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:

Endoscopy - Rate of 0-20%; coagulase-negative staphylococci (CoNS), streptococci,

diphtheroids
Colonoscopy - Rate of 0-20%; Escherichia coli, Bacteroides species
Barium enema - Rate of 0-20%; enterococci, aerobic and anaerobic gram-negative rods
Dental extractions - Rate of 40-100%; S viridans
Transurethral resection of the prostate - Rate of 20-40%; coliforms, enterococci, S aureus
Transesophageal echocardiography - Rate of 0-20%; S viridans, anaerobic organisms,
streptococci
The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than
doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the
placement of various types of central venous catheters. Hickman and Broviac catheters are associated
with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous
catheters are associated with similar rates.
Intravascular catheters are infected from 1 of the following 4 sources:

Infection of the insertion site

Infection of the catheter
Bacteremia arising from another site
Contamination of the infused solution
Bacterial adherence to intravascular catheters depends on the response of the host to the presence of
this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days
of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. S aureus adheres to the fibrin
component.
S aureus also produces an infection of the endothelial cells (endotheliosis), which is important in
producing the continuous bacteremia of S aureus BSIs. Endotheliosis may explain many cases of
persistent methicillin-susceptible S aureus (MSSA) and methicillin-resistant S aureus (MRSA) catheterrelated BSIs without an identifiable cause.
S aureus catheter-related BSIs occur even after an infected catheter is removed, apparently attributable
to specific virulence factors of certain strains of S aureusthat invade the adjacent endothelial cells. At
some point, the staphylococci re-enter the bloodstream, resulting in bacteremia. [13]
Four days after placement, the risk of infection markedly increases. Lines positioned in the internal jugular
are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous
tract is the most likely source of short-term catheter-related BSIs. Among lines in place for more than 2
weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a
reservoir of infection.

Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are
short-lived, are without consequence, and are often not preventable. Bacteria rarely adhere to an
endocardial nidus before the microorganisms are removed from the circulation by various host defenses.
Once microorganisms do establish themselves on the surface of the vegetation, the process of platelet
aggregation and fibrin deposition accelerate at the site. As the bacteria multiply, they are covered by everthickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses.
Organisms deep in the vegetation hibernate because of the paucity of available nutrients and are
therefore less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis.
Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction,
and various immunological mechanisms. The pathological picture of subacute IE is marked by valvular
vegetations in which bacteria colonies are present both on and below the surface.
The cellular reaction in SBE is primarily that of mononuclear cells and lymphocytes, with few
polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms.
Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of
destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to
perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little
extension of the infectious process occurs beyond the valvular leaflets.
levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly
increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of
the disease are due to circulating immune complexes. Among these include glomerulonephritis,
peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various
musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.
The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute
disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large
amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of
necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and
of the chordae tendineae.
The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection
produced by suppurative emboli. Because of their shortened course, immunological phenomena are not a
part of acute IE.
ETIOLOGY
The different types of IE have varying causes and involve different pathogens.

Native valve endocarditis

The following are the main underlying causes of NVE:

Rheumatic valvular disease (30% of NVE) - Primarily involves the mitral valve followed by the
aortic valve

Congenital heart disease (15% of NVE) - Underlying etiologies include a patent ductus arteriosus,
ventricular septal defect, tetralogy of Fallot, or any native or surgical high-flow lesion.

Mitral valve prolapse with an associated murmur (20% of NVE)

Degenerative heart disease - Including calcific aortic stenosis due to a bicuspid valve, Marfan
syndrome, or syphilitic disease
Approximately 70% of infections in NVE are caused by Streptococcus species, including S viridans,
Streptococcus bovis, and enterococci. Staphylococcusspecies cause 25% of cases and generally
demonstrate a more aggressive acute course (see the images below).

Prosthetic valve endocarditis

Early PVE, which presents shortly after surgery, has a different bacteriology and prognosis than late PVE,
which presents in a subacute fashion similar to NVE.
Infection associated with aortic valve prostheses is particularly associated with local abscess and fistula
formation, and valvular dehiscence. This may lead to shock, heart failure, heart block, shunting of blood to
the right atrium, pericardial tamponade, and peripheral emboli to the central nervous system and
elsewhere.
Early PVE may be caused by a variety of pathogens, including S aureus and S epidermidis. These
nosocomially acquired organisms are often methicillin-resistant (eg, MRSA). [14] Late disease is most
commonly caused by streptococci. Overall, CoNS are the most frequent cause of PVE (30%).
S aureus causes 17% of early PVE and 12% of late PVE. Corynebacterium,nonenterococcal streptococci,
fungi (eg, C albicans, Candida stellatoidea, Aspergillus species), Legionella, and the HACEK
(ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis,
Eikenella corrodens, Kingella kingae) organisms cause the remaining cases.

IVDA infective endocarditis

Diagnosis of endocarditis in IV drug users can be difficult and requires a high index of suspicion. Two
thirds of patients have no previous history of heart disease or murmur on admission. A murmur may be
absent in those with tricuspid disease, owing to the relatively small pressure gradient across this valve.
Pulmonary manifestations may be prominent in patients with tricuspid infection: one third have pleuritic
chest pain, and three quarters demonstrate chest radiographic abnormalities.
S aureus is the most common (< 50% of cases) etiologic organism in patients with IVDA IE. MRSA
accounts for an increasing portion of S aureus infections and has been associated with previous
hospitalizations, long-term addiction, and nonprescribed antibiotic use. Groups A, C, and G streptococci
and enterococci are also recovered from patients with IVDA IE.
Currently, gram-negative organisms are involved infrequently. P aeruginosa[15] and the HACEK family are
the most common examples.

Nosocomial/healthcare-associated infective endocarditis

Endocarditis may be associated with new therapeutic modalities involving intravascular devices such as
central or peripheral intravenous catheters, rhythm control devices such as pacemakers and defibrillators,
hemodialysis shunts and catheters, and chemotherapeutic and hyperalimentation lines. [16] These patients
tend to have significant comorbidities, more advanced age, and predominant infection with S aureus. The
mortality rate is high in this group.
The organisms that cause NIE/HCIE obviously are related to the type of underlying bacteremia. The
gram-positive cocci (ie, S aureus, CoNS, enterococci, nonenterococcal streptococci) are the most
common pathogens.

Fungal endocarditis
Fungal endocarditis is found in intravenous drug users and intensive care unit patients who receive
broad-spectrum antibiotics.[17] Blood cultures are often negative, and diagnosis frequently is made after
microscopic examination of large emboli.

Clinical features associated with different pathogens

Different causative organisms tend to give rise to varying clinical manifestations of IE, as shown in the
Table below.
Table 1. Clinical Features of Infective Endocarditis According to Causative Organism (Open Table in a
new window)

Causative Organism(s)

Clinical Features of IE

Staphylococcus aureus

Overall, S aureus infection is the most common cause of IE, including PVE, acute IE, and
IVDA IE.
Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE.
More than half the cases are not associated with underlying valvular disease.
The mortality rate of S aureus IE is 40-50%.
S aureus infection is the second most common cause of nosocomial BSIs, second only to
CoNS infection.
The incidence of MRSA infections, both the hospital- and community-acquired varieties,
has dramatically increased (50% of isolates). Sixty percent of individuals are intermittent carriers of
MRSA or MSSA .
The primary risk factor for S aureus BSI is the presence of intravascular lines. Other risk
factors include cancer, diabetes, corticosteroid use, IVDA, alcoholism, and renal failure.
The realization that approximately 50% of hospital- and community-acquired
staphylococcal bacteremias arise from infected vascular catheters has led to the reclassification of
staphylococcal BSIs. BSIs are acquired not only in the hospital but also in any type of health care facility
(eg, nursing home, dialysis center).
Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated
with intravascular catheters.

Streptococcus viridans

This organism accounts for approximately 50-60% of cases of subacute disease.

Most clinical signs and symptoms are mediated immunologically.

Streptococcus intermediusgroup

These infections may be acute or subacute.

S intermedius infection accounts for 15% of streptococcal IE cases.
S intermedius is unique among the streptococci; it can actively invade tissue and can cause
abscesses.

Abiotrophia

Group D streptococci

Approximately 5% of subacute cases of IE are due to infection withAbiotrophia species.

They require metabolically active forms of vitamin B-6 for growth.
This type of IE is associated with large vegetations that lead to embolization and a high rate
of posttreatment relapse.
Most cases are subacute.
The source is the gastrointestinal or genitourinary tract.
It is the third most common cause of IE.
They pose major resistance problems for antibiotics.

Nonenterococcal group D

The clinical course is subacute.

Infection often reflects underlying abnormalities of the large bowel (eg, ulcerative colitis,
polyps, cancer).
The organisms are sensitive to penicillin.

Group B streptococci

Acute disease develops in pregnant patients and older patients with underlying diseases (eg,
cancer, diabetes, alcoholism).
The mortality rate is 40%.
Complications include metastatic infection, arterial thrombi, and congestive heart failure.
It often requires valve replacement for cure.

Group A, C, and G streptococci

Acute disease resembles that of S aureus IE (30-70% mortality rate), with suppurative
complications.
Group A organisms respond to penicillin alone.
Group C and G organisms require a combination of synergistic antibiotics (as with
enterococci).

Coagulase-negative S aureus

This causes subacute disease.

It behaves similarly to S viridans infection.
It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.[18]

Pseudomonas aeruginosa

This is usually acute, except when it involves the right side of the heart in IVDA IE.
Surgery is commonly required for cure.

HACEK (ie, Haemophilus aphrophilus, Actinobacillus

actinomycetemcomitans, Cardiobacterium hominis,
Eikenella corrodens, Kingella kingae)

These organisms usually cause subacute disease.

They account for approximately 5% of IE cases.
They are the most common gram-negative organisms isolated from patients with IE.
Complications may include massive arterial emboli and congestive heart failure.
Cure requires ampicillin, gentamicin, and surgery.

Fungal

These usually cause subacute disease.

The most common organism of both fungal NVE and fungal PVE isCandida albicans.
Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis.
Aspergillus species are observed in fungal PVE and NIE.

Bartonella

The most commonly involved species is Bartonella quintana.

IE typically develops in homeless males who have extremely substandard

hygiene. Bartonella must be considered in cases of culture-negative endocarditis among homeless
individuals.
Multiple pathogens (polymicrobial)

Pseudomonas and enterococci are the most common combination of organisms.

It is observed in cases of IVDA IE
The cardiac surgery mortality rate is twice that associated with single-agent IE. [19]

Risk factors
The most significant risk factor for IE is residual valvular damage caused by a previous attack of
endocarditis.[20, 16]
Many possible risk factors for the development of pacemaker IE have been described, including diabetes
mellitus, age, and use of anticoagulants and corticosteroids. The evidence for these is conflicting. The
major risk factor is probably surgical intervention to any part of the pacemaker system, especially elective
battery replacements. The rate of infection associated with battery replacements is approximately 5 times
that of the initial implantation (6.5% vs 1.4%).
Other significant risk factors for pacemaker IE include the development of a postoperative hematoma, the
inexperience of the surgeon, and a preceding temporary transvenous pacing.

Rheumatic heart disease

Rheumatic heart disease is the most serious complication of rheumatic fever. Acute rheumatic fever
follows 0.3% of cases of group A beta-hemolytic streptococcal pharyngitis in children. As many as 39% of
patients with acute rheumatic fever may develop varying degrees of pancarditis with associated valve
insufficiency, heart failure, pericarditis, and even death. With chronic rheumatic heart disease, patients
develop valve stenosis with varying degrees of regurgitation, atrial dilation, arrhythmias, and ventricular
dysfunction. Chronic rheumatic heart disease remains the leading cause of mitral valve stenosis and
valve replacement in adults in the United States.
Acute rheumatic fever and rheumatic heart disease are thought to result from an autoimmune response,
but the exact pathogenesis remains unclear. Although rheumatic heart disease was the leading cause of
death 100 years ago in people aged 5-20 years in the United States, incidence of this disease has
decreased in developed countries, and the mortality rate has dropped to just above 0% since the 1960s.
Worldwide, rheumatic heart disease remains a major health problem. Chronic rheumatic heart disease is
estimated to occur in 5-30 million children and young adults; 90,000 individuals die from this disease each
year. The mortality rate from this disease remains 1-10%. A comprehensive resource provided by the
World Health Organization (WHO) addresses the diagnosis and treatment.
Pathophysiology
Rheumatic fever develops in some children and adolescents following pharyngitis with group A betahemolytic Streptococcus (ie, Streptococcus pyogenes). The organisms attach to the epithelial cells of the
upper respiratory tract and produce a battery of enzymes allowing them to damage and invade human
tissues. After an incubation period of 2-4 days, the invading organisms elicit an acute inflammatory
response with 3-5 days of sore throat, fever, malaise, headache, and an elevated leukocyte count.
In 0.3-3% of cases, infection leads to rheumatic fever several weeks after the sore throat has resolved.
Only infections of the pharynx initiate or reactivate rheumatic fever. The organism spreads by direct
contact with oral or respiratory secretions, and spread is enhanced by crowded living conditions. Patients
remain infected for weeks after symptomatic resolution of pharyngitis and may serve as a reservoir for

infecting others. Penicillin treatment shortens the clinical course of streptococcal pharyngitis and, more
importantly, is effective in decreasing the incidence of major sequelae.
Group A Streptococcus is a gram-positive coccus that frequently colonizes the skin and oropharynx. This
organism may cause suppurative disease, such as pharyngitis, impetigo, cellulitis, myositis, pneumonia,
and puerperal sepsis. It also may be associated with nonsuppurative disease, such as rheumatic fever
and acute poststreptococcal glomerulonephritis. Group A streptococci elaborate the cytolytic toxins
streptolysins S and O. Of these, streptolysin O induces persistently high antibody titers that provide a
useful marker of group A streptococcal infection and its nonsuppurative complications.
Group A Streptococcus, as identified using the Lancefield classification, has a group A carbohydrate
antigen in the cell wall that is composed of a branched polymer of L- rhamnose and N- acetyl-Dglucosamine in a 2:1 ratio.
Group A streptococci may be subserotyped by surface proteins on the cell wall of the organism. The
presence of the M protein is the most important virulence factor for group A streptococcal infection in
humans.
More than 120 M protein serotypes or M protein genotypes have been identified [2] , some of which have a
long terminal antigenic domain (ie, epitopes) similar to antigens in various components of the human
heart.
Rheumatogenic strains are often encapsulated mucoid strains, rich in M proteins, and resistant to
phagocytosis. These strains are strongly immunogenic, and anti-M antibodies against the streptococcal
infection may cross-react with components of heart tissue (ie, sarcolemmal membranes, valve
glycoproteins). Currently, emmtyping is felt to be more discriminating than M typing. [2]
Acute rheumatic heart disease often produces a pancarditis characterized by endocarditis, myocarditis,
and pericarditis. Endocarditis is manifested as valve insufficiency. The mitral valve is most commonly and
severely affected (65-70% of patients), and the aortic valve is second in frequency (25%). The tricuspid
valve is deformed in only 10% of patients and is almost always associated with mitral and aortic lesions.
The pulmonary valve is rarely affected. Severe valve insufficiency during the acute phase may result in
congestive heart failure and even death (1% of patients). Whether myocardial dysfunction during acute
rheumatic fever is primarily related to myocarditis or is secondary to congestive heart failure from severe
valve insufficiency is not known. Pericarditis, when present, rarely affects cardiac function or results in
constrictive pericarditis.
Chronic manifestations due to residual and progressive valve deformity occur in 9-39% of adults with
previous rheumatic heart disease. Fusion of the valve apparatus resulting in stenosis or a combination of
stenosis and insufficiency develops 2-10 years after an episode of acute rheumatic fever, and recurrent
episodes may cause progressive damage to the valves. Fusion occurs at the level of the valve
commissures, cusps, chordal attachments, or any combination of these. Rheumatic heart disease is
responsible for 99% of mitral valve stenosis in adults in the United States. Associated atrial fibrillation or
left atrial thrombus formation from chronic mitral valve involvement and atrial enlargement may be
observed.
Epidemiology

Frequency
United States
At this time, rheumatic fever is uncommon among children in the United States. Incidence of rheumatic
fever and rheumatic heart disease has decreased in the United States and other industrialized countries
in the past 80 years. Prevalence of rheumatic heart disease in the United States now is less than 0.05 per
1000 population, with rare regional outbreaks reported in Tennessee in the 1960s and in Utah [3] , Ohio,
and Pennsylvania in the 1980s. In the early 1900s, incidence was reportedly 5-10 cases per 1000
population. Decreased incidence of rheumatic fever has been attributed to the introduction of penicillin or
a change in the virulence of the Streptococcus. The incidence of acute rheumatic fever in other developed
countries, such as Italy, is comparable.[4]
International
In contrast to trends in the United States, the incidence of rheumatic fever and rheumatic heart disease
has not decreased in developing countries. Retrospective studies reveal developing countries to have the
highest figures for cardiac involvement and recurrence rates of rheumatic fever. Worldwide, there are over
15 million cases of RHD, with 282,000 new cases and 233,000 deaths from this disease each year.[5]
A study of school children in Cambodia and Mozambique with rheumatic fever showed that rheumatic
heart disease prevalence when echocardiography is used for screening is 10 fold greater compared with
the prevalence when clinical examination alone is performed. [6]

Mortality/Morbidity
Rheumatic heart disease is the major cause of morbidity from rheumatic fever and the major cause of
mitral insufficiency and stenosis in the United States and the world. Variables that correlate with severity
of valve disease include the number of previous attacks of rheumatic fever, the length of time between the
onset of disease and start of therapy, and sex. (The disease is more severe in females than in males.)
Insufficiency from acute rheumatic valve disease resolves in 60-80% of patients who adhere to antibiotic
prophylaxis.

Race
Native Hawaiian and Maori (both of Polynesian descent) have a higher incidence of rheumatic fever (13.4
per 100,000 hospitalized children per year), even with antibiotic prophylaxis of streptococcal pharyngitis.
Otherwise, race (when controlled for socioeconomic variables) has not been documented to influence
disease incidence.

Sex
Rheumatic fever occurs in equal numbers in males and females, but the prognosis is worse for females
than for males.

Age

Rheumatic fever is principally a disease of childhood, with a median age of 10 years, although it also
occurs in adults (20% of cases).