Carditis

Specific Educational Objectives: The student should be able to:

Recite the most common causes of these diseases.
Describe the common means of acquiring these diseases.
Describe the major manifestations.
Know Duke’s criteria in diagnosing endocarditis.
Know Jone’s criteria in diagnosing rheumatic fever

OVERVIEW

Four different diseases will be discussed in this handout. Three different diseases are associated with infections of the heart and they include; pericarditis, myocarditis, and endocarditis. Rheumatic heart disease is an inflammatory reaction that causes inflammation of the heart and can damage heart valves following pharyngeal infections with Streptococcus pyogenes.

Pericarditis is an infection of the pericardium. The pericardium is a barrier that protects the heart from infections that occur in nearby tissues. The pericardium consists of an outer fibrous layer and an inner serous layer. The fibrous pericardium is a tough sac that is attached to the diaphragm, sternum, and costal cartilage. The serous layer is thin and is the layer that is closest to the surface of the heart.

The potential space between the fibrous and serous layers of the pericardium contains about 20 ml of fluid. The fluid in the pericardial space is similar to plasma in protein and electrolyte composition. In most cases 120 ml of additional fluid can accumulate in the pericardium without an increase in pressure on the heart. However if more fluid accumulates in the pericardial space marked increases in pericardial pressure can occur. This increase in pericardial pressure can prevent the lower chambers of the heart from filling properly with blood. This can cause decreases in cardiac output followed by hypotension. The condition where cardiac output is decreased due to increases in pericardial pressure is called cardiac tamponade. Infections of the pericardium can cause accumulation of fluid in the pericardial space resulting in cardiac tamponade.

Three different types of pericarditis will be discussed in this handout; viral, purulent, and chronic pericarditis (Table C-1). In the United States, viral pericarditis is the most common cause of pericardial infection.

Table C-1. Common Infectious Causes of Heart Disease
Disease	Common Infectious Cause(s)	Infection or Inflammatory Reaction to Infection
Viral pericarditis	Enteroviruses- coxsackieviruses A and B, and Echovirus	Infection
Purulent pericarditis	Staphylococcus aureus, Streptococcus pneumoniae	Infection
Chronic pericarditis	Mycobacterium tuberculosis	Infection
Myocarditis	Coxsackieviruses B	Infection
Subacute infective endocarditis	Streptococcus species	Infection
Acute infective endocarditis	Staphylococcus aureus	Infection
Acute rheumatic heart disease	Streptococcus pyogenes	Inflammatory Reaction to Infection

Myocarditis is defined as inflammation of the myocardium and is characterized by myocyte necrosis. Myocarditis can occur following infection (e.g., virus), toxic exposure (e.g., zidovudine, hypersensitivity to penicillin) and autoimmune reactions (e.g., systemic lupus erythematosus). The infections of the heart that result in myocarditis will be discussed in this handout. Just as viruses are the most common cause of pericarditis they are also the most common cause of myocardial infection (Table C-1).

Endocarditis is an inflammation of the inner surface or endothelium of the heart. The surfaces most commonly affected in endocarditis are the surfaces of the heart valves. Endocarditis can be classified as infective or non-infective. Non-infective endocarditis is very rare and can follow autoimmune reactions (e.g., Libman-Sacks endocarditis) or can occur in patients with mucinous adenocarcinoma. Infective endocarditis will be discussed in this handout and can be further subdivided into subacute and acute endocarditis. Bacteria are the most common causes of both subacute and acute endocarditis (Table C-1).

Acute rheumatic fever is an autoimmune reaction to the heart, joints, central nervous system, skin, and subcutaneous tissues following an untreated pharyngitis caused by Streptococcus pyogenes (Table C-1). The most serious complication of acute rheumatic fever is rheumatic heart disease that causes carditis and valvulitis. Acute rheumatic fever and rheumatic heart disease will also be discussed. Although rheumatic heart disease is rare it is still the leading cause of mitral valve insufficiency and stenosis in the U.S. This autoimmune reaction is always a concern in children with untreated pharyngitis caused by Streptococcus pyogenes.

PERICARDITIS

Pericarditis is an inflammation of the fibroserous sac enclosing the heart and has multiple infectious and noninfectious causes. There are three different types of infectious pericarditis: viral pericarditis, purulent pericarditis (also called acute bacterial pericarditis), and chronic pericarditis (also called tuberculous pericarditis).

Etiology

Viruses are the most common cause of pericarditis. The viruses that most commonly cause viral pericarditis are the Enteroviruses (i.e., Coxsackieviruses A and B and Echovirus). Less common causes of viral pericarditis include: herpes viruses, adenoviruses, influenza virus, human immunodeficiency virus, and mumps virus.

Purulent pericarditis is quite rare with the most common causes being Staphylococcus aureus, Streptococcus pneumoniae, and other streptococci. Chronic pericarditis is also rare and is caused by Mycobacterium tuberculosis and fungi (e.g., Candida).

Manifestations

The signs and symptoms of pericarditis vary depending upon the cause of the infection.

Viral pericarditis usually presents with sharp substernal chest pain that is made worse by inspiration. Pain is also worsened by lying supine. The patient prefers to sit up and lean forward to lessen the pain.

The signs and symptoms of purulent pericarditis develop suddenly and include fever and dyspnea. Only about one third of the patients have the chest pain described in viral pericarditis. Unfortunately, there are no specific symptoms in many cases and this infection is oftentimes misdiagnosed.

Tuberculous pericarditis has the most insidious clinical onset. The patient may have vague, dull chest pain, weight loss, night sweats, cough, and dyspnea.

Physical findings in all three types of pericarditis depend on how much exudate accumulates in the pericardial space (See Table P-1 and Table P-2).

Table P-1. Signs that Maybe Present in Viral, Purulent, or Chronic Pericarditis
Sign	Comments
Friction rub	Is usually auscultated early when little fluid is in space. As more fluid accumulates the sound goes away.
Pulsus paradoxicus	A drop in peak systolic blood pressure of more than 20 mm Hg on inspiration. Finding associated with cardiac tamponade.
Kussmaul's sign	A paradoxical increase in venous distention and pressure during inspiration. Finding associated with cardiac tamponade.
Jugular venous distention and abnormal jugular venous pulsations	Finding associated with cardiac tamponade.
Ewart's sign	An area of dullness to percussion at the tip of the left scapula
Decreased or muffled heart sounds	More common when large amounts of fluid are in the pericardium.
Abnormal Electrocardiographs (i.e., ECG or EKG)	ECG’s from a patient with pericarditis can be quite similar to patients with an acute myocardial infarction or in someone with normal-variant repolarization abnormality. In a patient with pericarditis the ST segment is elevated in all leads. The ST-segment elevation shows upward concavity (so-called "smiling face"). The PR interval is depressed. See Table P-2 to see the differences in the ECG in these three conditions.

Table P-2. Electrocardiograph Segment or Shape Changes in Acute Purulent Pericarditis, Acute Myocardial Infarction, and Normal-Variant Repolarization Abnormality
ECG segment or shape change	Acute purulent pericarditis	Acute myocardial infarction	Normal-variant repolarization abnormality
ST-segment	ST-segment elevation in all leads, with no ST-segment depression	ST-segment elevation in anatomically contiguous leads, with reciprocal ST-segment depression	ST-segment elevation in middle and left precordial leads, but may be widespread with no reciprocal ST-segment depression
ST-segment shape	Upward concave ST-segment elevation (“Smiling Face”)	Upward convex ST-segment elevation	Upward convex ST-segment elevation
T-wave	No T-wave inversion in leads with ST-segment elevation	T-wave inversion in leads with ST-segment elevation as myocardial infarction evolves	May have T-wave inversion in leads with ST-segment elevation
PR-segment	PR-segment depression	No PR-segment depression	No PR-segment depression
Q waves	Q waves during evolution	May have Q waves during evolution	No Q waves

Epidemiology

Pericarditis is a relatively common disease with various autopsy series revealing 2-6% of people with pericardial inflammation.
Only 1 out of every 1000 hospital admissions is diagnosed clinically as pericarditis.
Many idiopathic pericarditis cases are believed to be viral in origin and occur in the spring and autumn coincident with outbreaks of enteroviral disease.
Mortality rate is more common in acute purulent pericarditis than viral pericarditis. The mortality rate exceeds 50% in untreated acute purulent pericarditis and even with appropriate therapy the mortality rate is around 30%.
Viral pericarditis is usually acquired following ingestion of fecally contaminated food or water.
Purulent pericarditis can occur following spread of a localized infection to the pericardium (e.g., lung infections), surgery, or as a result of a bacteremia.
Chronic pericarditis can be acquired following inhalation of M tuberculosis and spread of the organism from the lungs to the blood stream and then to the pericardium. About 5% of patients with pulmonary tuberculosis will have pericardial involvement.

Pathogenesis

In most cases of pericarditis the microorganisms reach the pericardium by the blood stream. Rarely the organism will enter the pericardium by direct extension from the lung or direct inoculation during surgery, invasive medical procedures, or trauma. The organism colonizes the pericardium and stimulates an inflammatory reaction. If the infecting organism is a virus viral cell lysis can also follow. The inflammatory reaction results in the accumulation of serous (i.e., viral pericarditis) or purulent exudate (i.e., purulent pericarditis), which may in turn cause cardiac tamponade (the exertion of pressure or compression of the heart) and circulatory failure.

Tuberculous pericarditis results from hematogenous spread during primary disease. It can spread to the pericardium by lymphatic drainage from the respiratory tract or via direct spread from the lungs or pleura.

Viral infections often infect the myocardium as well as the pericardium. Bacterial pathogens like Streptococcus pneumoniae usually infect the pericardium by extension from an adjacent pneumonitis. The common causes of bacteremias, staphylococci, meningococci, and Haemophilus influenzae are more likely to reach the pericardium through the blood stream. Postoperative infections are most commonly caused by Staphylococcus aureus, gram-negative aerobic rods, or Candida.

In viral pericarditis the viruses causing this disease produce a relatively mild inflammatory reaction that is associated with focal damage to the adjacent myocardium. The fluid in the pericardial space can vary. There can be a small amount of serous fluid with mononuclear cells and fibrinogen to a large amount of, neutrophil-rich, bloody effusion fluid. Tissue damage is the result of direct cellular damage by the infecting virus, destruction of viral-infected cells by sensitized T-lymphocytes, and antibody-dependent, cell-mediated cytotoxicity.

Mild fibrosis and occasional adhesions between visceral and parietal surfaces of the pericardium may occur following resolution of the viral pericarditis. However, such a fibrotic reaction rarely gives rise to a constrictive pericarditis. The disease is self-limiting and rarely fatal.

In purulent pericarditis the bacteria that cause this disease usually invoke a strong rapidly progressing purulent immune reaction. The purulent material in the pericardial space contains large numbers of polymorphonuclear leukocytes in a large volume of effusion fluid. The tissue damage is the result of toxin and enzyme production by the bacteria and rapidly progressing cardiac tamponade. Healing is associated with extensive fibrosis that may progress to a chronic, constrictive pericarditis.

Chronic pericarditis is most commonly caused by M tuberculosis. The early granulomatous stages of this infection are associated with large pericardial effusions (> 300 ml) that are typically serosanguinous and contain a predominance of mononuclear cells. As the disease evolves, the inflammatory process becomes chronic; fusion of the parietal and visceral pericardium frequently occurs, causing constrictive pericarditis and circulatory failure.

Diagnosis

Determining the cause in viral pericarditis is difficult and not usually done. The unique presentation of substernal pain that is worse during inspiration or when the patient is lying down and is relieved by leaning forward is helpful in making the diagnosis. Chest radiographs can be used to reveal the flask-shaped, enlarged cardiac silhouette due to large amounts of fluid being present in the pericardium. Echocardiography can detect pericardial thickening and pericardia fluid accumulation. Electrocardiographs (ECG’s) in acute purulent pericarditis can be similar to patients with acute myocardial infarction or normal-variant repolarization abnormality. See table P-2 for help in determining which change in the ECG is due to pericarditis. In cardiac tamponade, the ECG may show electrical alternans associated with cardiac motion as the heart "floats" in relation to the recording leads. Electrical alternans is alternate-beat variation in the direction, amplitude, and duration of any component of the ECG waveform (i.e., P, PR, QRS, R-R, ST, T, U). Chronic constrictive pericarditis presents with low voltage of the QRS complex and diffuse flattening or inversion of the T waves. Atrial fibrillation occurs in one third of patients with pericardial disease. Pericardiocentesis can be used in some cases (e.g., purulent pericarditis with cardiac tamponade) to culture for the infecting agent.

Therapy and Prevention

Supportive care is indicated in patients with viral pericarditis. Nonsteroidal anti-inflammatory agents can be used to reduce chest pain. However, they should be avoided if the patient also has myocarditis. In patients with purulent pericarditis surgical drainage of the fluid in the pericardium (i.e., pericardiocentesis) and systemic antibiotics are important in helping the patient resolve the infection. The antibiotic chosen depends on the organism that is causing the purulent pericarditis. Until the cause is identified antibiotics used to treat this infection include a penicillinase resistant beta-lactam antibiotic and a third generation cephalosporin (Table P-3). To treat chronic pericarditis due to M tuberculosis a four drug regimen is recommended that includes isoniazid, ethambutol, rifampin, and pyrazinamide. Since constrictive pericarditis is more common in chronic pericarditis prednisone is also utilized to prevent constriction. If calcifications form pericardectomy is required.

Table P-3. Antibiotic Therapy for Acute Purulent Pericarditis and Microbial Coverage*
Penicillinase-resistant beta-lactam	Microbial coverage	Third generation cephalosporins	Microbial coverage
Oxacillin	Good gram positive coverage; effective against penicillinase producing staphylococci; poor gram negative coverage	Cefotaxime	Good gram negative coverage, poor gram positive coverage
Methicillin	Good gram positive coverage; effective against penicillinase producing staphylococci; poor gram negative coverage	Ceftriaxone	Good gram negative coverage, poor gram positive coverage
Nafcillin	Good gram positive coverage; effective against penicillinase producing staphylococci; better gram negative coverage than other two beta-lactams above
*Empiric therapy usually includes the use of one penicillinase beta-lactam antibiotic and a third generation cephalosporin.

MYOCARDITIS

Myocarditis is an infection of the myocardium or myocytes in the heart. The virus is ingested in fecally contaminated water or food and eventually reaches the heart.

Etiology

Many species of viruses, bacteria, Chlamydia, Rickettsia, fungi and protozoans can cause myocarditis. However, viruses are the most important infectious agents. Of these, the Enteroviruses are the single most important group with coxsackieviruses B being the most common cause of myocarditis in the U.S. Other viruses have been implicated in causing myocarditis and include the herpes viruses and mumps virus. Patients with asymptomatic HIV infection have a high incidence of myocarditis.

Bacterial and fungal organisms can cause myocarditis but are rare in the U.S. Other than identifying the common agents they will not be discussed further. Bacterial causes of myocarditis include Legionella, Chlamydia, and Borrelia burgdorferi. Fungal causes of myocarditis include Aspergillus, Candida, and Cryptococcus. Parasitic causes of myocarditis include Trypanosoma cruzi and Trichinella spiralis.

Manifestations

Most persons with myocarditis are asymptomatic. If symptoms are present the pace of the illness and the symptoms vary greatly. Symptoms include; flu-like illness with chest pain when the pericardium is involved, arrhythmias, or signs of right- and left-sided congestive heart failure. Patients with myocarditis oftentimes present with signs and symptoms of acute decompensation of heart failure (e.g., tachycardia, gallop, mitral regurgitation, and edema) and pericardial friction rub in those with concomitant pericarditis. Left ventricular dilatation can lead to expansion of the mitral valve ring and a mitral regurgitant murmur. A S3 gallop indicates left-sided congestive heart failure.

Epidemiology

Forced exercise, pregnancy, use of steroids or nonsteroidal anti-inflammatory agents, use of ethanol, and nutritional deficiencies are factors that predispose a patient to symptomatic myocarditis.
The incidence of myocarditis is estimated at 1-10 cases per 100,000 persons.

Pathogenesis

Viruses directly invade the myocytes and cause damage to the infected cells. The immune response to infection also causes damage to the myocytes. Immune cell infiltration of the myocytes includes T-lymphocytes predominantly accompanied by macrophages and B-lymphocytes. Circulating autoantibodies directed against mitochondria and contractile proteins are frequently detected and may cause further damage. Cytokines and oxygen free radicals have also been implicated in causing damage to the myocytes.

Diagnosis

Diagnosis of myocarditis involves identifying the signs and symptoms of cardiac failure. A peripheral blood complete blood count usually reveals a leukocytosis. About 50% of patients with myocarditis will have elevated levels of cardiac troponin I and about 5% of patients will have elevated levels of creatine kinase-MB in their blood stream. They usually have an elevated erythrocyte sedimentation rate and increased levels of acute phase proteins in their blood stream (e.g., C-reactive protein, complement, alpha 2-macroglobulin). EKG’s can be obtained but are usually nonspecific and if abnormal may demonstrate ST and T wave changes, ventricular or atrial arrhythmias, and conduction defects. Chest radiographs can be used to detect pulmonary edema in congestive heart failure and cardiac dilatation. Echocardiography can be used to assess cardiac contractility, chamber size, valve function, and wall thickness and to exclude other causes of heart failure (e.g., valvular, amyloidosis, congenital). Contrast-enhanced MRI can detect the extent and degree of inflammation and determines parameters that correlate with left ventricular function and clinical status. To obtain a definitive diagnosis an endomyocardial biopsy is needed however this is not usually done.

Therapy and Prevention

Most cases of viral myocarditis are self-limited and are followed by full recovery. Viral myocarditis is usually a mild disease and responds well to bed rest. Cardiac monitoring may be required to alert caregivers to potentially life-threatening arrhythmias. Glucosteroids and other immunosuppressive drugs are contraindicated.

ENDOCARDITIS

Endocarditis is an inflammation of the endothelium that lines the inside of the heart. Certain areas of the endothelium are more likely to be affected in endocarditis and they include the surfaces of the heart valves. Some heart valves are more commonly affected than others.

Etiology

The etiology of endocarditis depends on the condition of the heart valve, if the person is an intravenous drug user, if the patient has a prosthetic heart valve, and how long the prosthetic heart valve has been in place (See Table E-1).

Table E-1. Causes of Endocarditis by Type of Heart Valve or Patient Condition
Type of heart valve or patient condition	Common causes (percent of patients with that etiology)	Infrequent causes
Native heart valve	Streptococcus (i.e., viridans streptococci, Streptococcus bovis), Staphylococcus (usually Staphylococcus aureus), Enterococcus	Gram-negative bacilli, HACEK group (Haemophilus aphrophilus Haemophilus parainfluenzae or Haemophilus paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), Coxiella burnetii, and Chlamydia
Prosthetic valve infections Early (within 2 months of heart surgery)	Staphylococcus (Staphylococcus aureus and Staphylococcus epidermidis), gram-negative aerobic bacilli	Fungi
Prosthetic valve infections Late (more than 2 months post heart surgery)	Viridans Streptococcus, Staphylococcus epidermidis, and Staphylococcus aureus	Gram-negative bacilli and fungi
Intravenous drug users	Staphylococcus aureus and gram-negative bacilli (Pseudomonas aeruginosa is most the common gram-negative bacilli)	Viridans Streptococcus, Enterococcus, Candida albicans, polymicrobial infections

Manifestations

Two types of infectious endocarditis occur: subacute and acute. Subacute endocarditis is more common and takes more time for symptoms to develop. Oftentimes the symptoms are nonspecific. Acute endocarditis progresses very rapidly with more severe symptoms. Acute endocarditis is more common in intravenous drug users and in staphylococcal infections of the heart.

In subacute endocarditis the interval between the colonization of the endocardium and the onset of symptoms is usually less than two weeks. Because the symptoms are usually nonspecific, on average there is a delay of five weeks between onset of symptoms and diagnosis. The most common symptom is a low-grade fever (range of 38oC). Only in acute endocarditis does the temperature go above 40oC. Fever is usually accompanied by chills and sometimes by night sweats. Fatigue, anorexia, weakness, myalgias, arthralgias and malaise are common. Debilitating low back pain is a prominent complaint in a small percentage of patients.

Acute endocarditis has a rapid onset (e.g., hours to days) of signs and symptoms. Acute endocarditis is usually caused by Staphylococcus aureus or Enterococcus. The patient usually has a high fever is high (40oC) and rigors. Patients are very ill appearing. The likelihood of extravascular complications is higher.

The following signs and symptoms can be seen in patients with subacute or acute endocarditis. Nearly all patients will have an audible heart murmur. Although classically described as a changing murmur the murmur usually does not change significantly over time unless a valve leaflet is destroyed or a chordae tendineae ruptures. Murmurs are less common in right-sided endocarditis.

Roth spots or flame-shaped hemorrhages may be observed on funduscopic examination. Roth spots are retinal hemorrhages with pale centers. Petechial hemorrhages can occur in the conjunctiva, the buccal mucosa, palate, extremities, and splinter hemorrhages under the nail beds of the hands and feet. Janeway lesions are painless hemorrhagic plaques on the palms and soles. Osler nodes are small, pea-sized subcutaneous, painful erythematous nodules that occur in the pads of the fingers and toes and the thenar eminence. They are usually present for a brief period of time lasting only a few hours to a couple of days.

Complications occur in most patients and include cardiac complications (e.g., congestive heart failure, destruction of a heart valve, perivalvular extension of infection) and complications due to emboli (e.g., mycotic aneurysms, neurologic complications, renal complications).

Epidemiology

Infective endocarditis is a relatively uncommon infection. The incidence is around 2/100,000.
Endocarditis is more common in males than females and the disease is becoming more a disease of the elderly.
Microorganisms growing in the normal flora of the body cause most cases of infective endocarditis (e.g., mouth, intestine, skin).
Patients with prior valvular defects or those with an artificial heart valve are more likely to develop endocarditis following lip or tongue piercing.
Intravenous drug users commonly have infective endocarditis due to Staphylococcus aureus from contaminated needles.

Pathogenesis

Infective endocarditis is usually preceded by the formation of a predisposing cardiac lesion. Endothelial cells that line the inside of the heart and the heart valve can become damaged leading to the accumulation of platelets and fibrin producing a nonbacterial thrombotic endocarditis (NBTE). This sterile lesion serves as an ideal site for bacteria to attach to when in the bloodstream. Various conditions lead to endothelial cell damage and predispose a patient to the formation of NBTE. They include: rheumatic heart disease, congenital heart disease (i.e., bicuspid aortic valve, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot), mitral valve prolapse, degenerative heart disease (e.g., calcific aortic valve disease) and prosthetic valve placement. Intravenous drug users are at higher risk of developing endocarditis due to their propensity to inject bacterially contaminated solutions intravenously. Patient recovering from endocarditis are also at increased risk of having a second episode of endocarditis.

Shear stress can also damage the surface of the valves. The valves that get the most shear stress are the ones on the left side of the heart (i.e., mitral and aortic valves). With the exception of intravenous drug users right-sided endocarditis is uncommon. When right-sided endocarditis does occur it is usually on the tricuspid valve. Propensity to develop vegetations following trauma occurs as follows mitral>aortic>tricuspid >pulmonary valve.

Microorganisms growing in the normal flora of the body cause most cases of infective endocarditis. They gain access to the blood intermittently, as a result of minor trauma to the mucosa of the oropharynx, gastrointestinal tract, or genitourinary tract. Such transient bacteremias usually occur without ill effects but they may lead to endocarditis in patients with an underlying NBTE or artificial heart valve.

Bacteria and platelets tend to accumulate on the downstream or low-pressure side of a valvular NBTE. When bacteria colonize the NBTE they form vegetations. Surface adherence factors are essential for the bacteria to colonize the NBTE (e.g., Streptococcus sanguis binds to platelet receptors. Staphylococcus aureus binds to fibronectin.). Colony counts in the vegetations are usually 1,000,000,000-100,000,000,000 bacteria/gm of tissue. The bulk of the vegetation is an amorphous mass of fibrin and platelets containing colonies of microorganisms. These vegetations vary in size from tiny bodies to masses large enough to occlude valve orifices. Abscesses may develop by direct invasion of the valve rings of the heart near the vegetations. These are common with pyogenic cocci (e.g., staphylococci and streptococci) but rare with other organisms.

These vegetations are usually soft and friable and only loosely attached to the endocardium and they break off to form arterial emboli. These emboli can severely affect perfusion of the tissue down stream to the embolus causing infarcts in the tissues. Apart from the propensity to generate emboli, there is no correlation between size of vegetation and severity of endocarditis.

There are four consequences to the formation of the valvular vegetations.

Organisms within the vegetation are protected from elimination by antibodies, complement, and leukocytes and can live for long periods of time in the vegetation (e.g., weeks to months).
Organisms within the vegetation are metabolically inactive, replicating at an unusually slow rate. Many antibiotics require the bacteria to rapidly replicate to kill the microorganisms. Since the bacteria in the vegetation replicate very slowly the bacteria are much less sensitive to killing by antibiotics. This requires long periods of antimicrobial treatment (e.g., 4-6 weeks).
Healing is slow because macrophages and fibroblasts must spread through the vegetation and endothelial cells grow over the surface of the vegetation.
Emboli are generated when vegetations break off and these emboli can cause infarcts in other tissues (e.g., brain, kidney, extremities).

Diagnosis

Diagnosis of subacute endocarditis can be very difficult and is oftentimes misdiagnosed. Acute endocarditis can rapidly cause irreversible damage to the heart valves and needs to be diagnosed and aggressively treated.

Lab values of endocarditis are oftentimes nonspecific and can include:

Anemia of chronic disease in patients with subacute endocarditis (i.e., normocytic and normochromic erythrocytes, low serum iron, and low iron binding capacity).
Peripheral leukocyte count usually is normal except when myocardial abscesses occur, if an extravascular site of infection exists, or the patient has acute endocarditis.
Erythrocyte sedimentation rate and C-reactive protein are elevated in subacute and acute endocarditis.
About 50% of patients are positive for rheumatoid factor in subacute endocarditis.
Cryoglobulins, depressed complement levels, and false positive serology for syphilis can sometimes occur in subacute endocarditis
Urinalysis is usually abnormal (proteinuria and hematuria) in subacute and acute endocarditis.

The following tests will help in confirming the diagnosis of endocarditis. Transesophageal echocardiography (TEE) is the most sensitive and can detect vegetations as small as 3 mm. It readily detects extra-valvular extension of infection and can visualize valve perforations. Doppler color flow analysis allows for assessment of valve function, myocardial contractility and chamber volume. This information is important in deciding if surgery is needed.

Chest radiographs may demonstrate distinct round cannonball-like pulmonary emboli in right-sided endocarditis. Pulmonary edema may be present in those with acute mitral regurgitation or decompensated left-sided heart failure due to aortic valve regurgitation.

ECG’s should be obtained and closely monitored for conduction defects and blood cultures are critical for making the diagnosis. Infective endocarditis is associated with a constant low-level bacteremia. Obtain 3 blood samples (at least 10 ml of blood) at least 15 minutes between each blood letting over a 24-hour period. If the patient is acutely ill do this over a 45-minute period of time. The diagnosis is confirmed if good bacterial growth from the blood samples is obtained and if damage to the heart valves is detected by TEE. Modified Duke criteria can be utilized if the diagnosis cannot be confirmed (Table E-2).

Table E-2 Modified Duke Criteria for the Diagnosis of Bacterial Endocarditis
Definitive Diagnosis	Possible Diagnosis	Major Criteria	Minor Criteria
2 major criteria or 1 major criterion and 3 minor criteria or 5 minor criteria	1 major criterion and 1 minor criterion or 3 minor criteria	Two separate blood cultures that are both positive for typical endocarditis- associated organisms, including S aureus OR persistent positive blood cultures—two more that 12 hours apart, or all of three or a majority from among more that four, during 1 hour. Evidence of endocardial involvement by positive echocardiogram OR new regurgitant murmur Positive Q fever serology (antiphase I IgG > 1:800), or single blood culture positive for Coxiella burnetii	Predisposing heart disease or injection drug use Fever > 38 degrees C Vascular phenomenon: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial or conjunctival hemorrhage, Janeway lesions Immunologic phenomenon: glomerulonephritis, Osler's nodes, Roth's spots, rheumatoid factor Single positive blood culture with typical organisms Previous minor criterion of suspicious lesion on TTE now eliminated.

Therapy and Prevention

Antibiotic therapy must be given for 4 to 6 weeks, even if symptoms disappear prior to that time. A combination of antibiotics, rather than a single antibiotic, is always used. If no organism has been isolated after repeated attempts the recommended empiric therapy for subacute bacterial endocarditis is ampicillin and gentamicin. One exception to the 4 to 6 week treatment is subacute bacterial endocarditis caused by viridans Streptococcus in which the combination of penicillin G and gentamicin for two weeks works as well as treatment for 4 weeks. Empiric therapy for acute bacterial endocarditis includes vancomycin, ampicillin, and gentamicin.

If an organism has been isolated, then the antibiotic regimen is based on the species of the etiologic agent, the age of the patient and the extent of the disease. The regimens are complex and will not be discussed in this handout. If antibiotic therapy is not successful surgical removal of infected endocardium may be necessary.

RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

During the early 1900’s rheumatic fever and the most serious complication associated with this fever, rheumatic heart disease, were quite common. Rheumatic heart disease affected 5-10 people out of 1000 during this time. Rheumatic fever is still the leading cause of mitral valve insufficiency and stenosis in the U.S. Rheumatic heart disease oftentimes produces a pancarditis that can result in pericarditis, myocarditis and endocarditis.

Etiology

Streptococcus pyogenes (group A Streptococcus) is the etiological agent that induces an autoimmune reaction that results in damage to the heart. This complication occurs several weeks after a pharyngeal infection with S pyogenes. Skin infections (e.g., impetigo, cellulitis) with this organism do not cause rheumatic fever or rheumatic heart disease.

Manifestations

Acute rheumatic fever symptoms precede acute rheumatic heart disease. Acute rheumatic fever symptoms can occur within a few days to 5 weeks after a S pyogenes pharyngeal infection. The patient first presents with fever (38.3- 40°C) and migratory polyarthritis that usually is in the knees, elbows, or wrists. Other findings can include subcutaneous nodules, skin lesions (i.e., erythema marginatum; a serpiginous rash), chorea (i.e., rapid, purposeless movements of the face and upper extremities) and carditis.

Pancarditis is the most serious complication associated with rheumatic fever and is the second most common complication (50%). The most common complication is polyarthritis. In severe cases, patients may complain of dyspnea, mild-to-moderate chest discomfort, pleuritic chest pain, edema, cough, or orthopnea. Carditis is most commonly detected when a new heart murmur has been auscultated or when tachycardia out of proportion to the fever is observed. The heart murmurs are usually due to valvular insufficiency and the valve most frequently affected is the mitral valve followed by the aortic valve, then the tricuspid valve, or very rarely the pulmonary valve (notice the similarity of the order of the valves affected with that seen in infectious endocarditis). New or changing murmurs are necessary for a diagnosis of rheumatic valvulitis. Patients with chronic rheumatic heart disease can develop valve stenosis with varying degrees of regurgitation, atrial dilation, arrhythmias and ventricular dysfunction.

The patient may also manifest symptoms of congestive heart failure (tachypnea, orthopnea, jugular venous distention, rales, hepatomegaly, a gallop rhythm, and peripheral swelling and edema) or pericarditis (see symptoms in pericarditis section above).

Epidemiology

In 0.3-3% cases of untreated streptococcal pharyngitis, infection induces the host’s immune system to produce antibodies that damage host tissue and elicit the symptoms of acute rheumatic fever.
Rheumatic fever is principally a disease of childhood, with a median age of 10 years, although it can also occur in adults (20% of cases).
Rheumatic fever affects both males and females equally in numbers, but the prognosis is worse for females than for males.
Native Hawaiian and Maori have a higher incidence of rheumatic fever than other ethnic groups.
Prevalence of rheumatic heart disease in the U.S. is less than 5 per 100,000 population. The increased use of antibiotics in treating streptococcal pharyngitis and the change in virulence of the bacterial strains circulating in the population are believed to be the primary reasons for the lower prevalence.
The incidence of rheumatic fever and heart disease has not decreased in developing countries of the world. Worldwide about 5-30 million children and young adults have chronic rheumatic heart disease and 90,000 patients die from this disease annually.
Chronic rheumatic heart disease remains the leading cause of mitral valve stenosis and valve replacement in adults in the U.S.
Valvular insufficiency from acute rheumatic heart disease resolves in 60-80% of patients who adhere to antibiotic prophylaxis.
Chronic valvular disease can result in progressive valve deformity in adults with previous rheumatic heart disease. Fusion of the valve apparatus results in stenosis or a combination of stenosis or insufficiency and can develop 2-10 years after an episode of acute rheumatic fever.
Recurrent episodes of acute rheumatic fever can cause progressive damage to the valves.
Patients tend to have more severe rheumatic heart disease if they have had a number of previous episodes of rheumatic fever, the length of time between the onset of disease and start of therapy was greater than 10 day, or if the patient is female.
Antibiotic treatment shortens the clinical course of streptococcal pharyngitis, prevents acute rheumatic fever, and the suppurative sequelae (i.e., peritonsillar abscess, cervical lymphadenitis, and mastoiditis).
S pyogenes is spread by direct contact with oral or respiratory secretions and crowded living conditions increase person to person spread.
Patients can be colonized by the organism even weeks after symptomatic resolution of pharyngitis and they may serve as a reservoir for infecting others.

Pathogenesis

Acute rheumatic fever is an autoimmune response to the heart, joints, central nervous system, skin, and subcutaneous tissues. It is characterized by an exudative and proliferative inflammatory lesion of these tissues.

Following a S pyogenes pharyngitis the host’s immune system produces antibodies that cross react with bacterial antigens and with certain host tissues. Certain rheumatogenic strains of this S pyogenes are more likely to cause the host to produce these cross reactive antibodies and the host tissues most likely to be affected are the heart (i.e., pancarditis, valvulitis), joints (i.e., polyarthritis), central nervous system (i.e., chorea), skin (i.e., erythema marginatum) and subcutaneous tissues (i.e., subcutaneous nodules). Two bacterial factors appear to be important in the development of pharyngitis and in acute rheumatic fever and heart disease; hyaluronic acid capsule and M protein.

The hyaluronic acid capsule protects the bacteria from phagocytosis. However, it is identical to the hyaluronic acid found in the host’s connective tissues. If antibodies are produced to the bacteria’s capsule then these antibodies can also cause pathology in the host.

S pyogenes can be classified by the type of M-protein it produces. Over 100 serotypes of the M-protein have been identified and this protein is important in adherence to host epithelial cells, internalization in host cells, and avoidance of phagocytosis. M-proteins are subdivided into class I and class II. Rheumatogenic strains of S pyogenes are usually encapsulated strains rich in class I M-proteins. These rheumatogenic strains are highly immunogenic and anti–M protein antibodies can cross react with heart tissue. Other streptococcal antigens structurally similar to host tissues include cell wall polysaccharides (similar to glycoproteins in heart valves) and membrane antigens that share epitopes with the sarcolemma in striated muscle cells and smooth muscle.

Diagnosis

Rheumatic fever is a difficult diagnosis and the Jones Criteria are frequently used to help in making this diagnosis (Table R-1). Auscultation of the heart for heart murmurs, friction rubs, gallops, and irregular rhythms together with the signs and symptoms mentioned above help make the diagnosis of rheumatic heart disease more likely. Chest radiographs can reveal an enlarged heart and transesophageal echocardiography can reveal heart valve regurgitation and stenosis. Synovial fluid analysis may demonstrate an elevated white blood cell count with no crystals or organisms.

	Table R-1. Jones Criteria for Guidance in the Diagnosis of Rheumatic Fever*
	Major Manifestations	Minor Manifestations
	Carditis	Clinical
	Polyarthritis	Previous rheumatic fever or rheumatic heart disease
	Chorea	Arthralgia
	Erythema marginatum	Fever
	Subcutaneous nodules	Laboratory
		Acute phase reactants: increased erythrocyte sedimentation rate, increased levels of C-reactive protein in the blood, leukocytosis in a complete blood count
		Prolonged P-R interval in electrocardiograph (EKG)
	The presence of 2 major criteria or 1 major and 2 minor criteria, indicates a high probability the patient has acute rheumatic fever, if supported by evidence of preceding group A streptococcal infection*.
	**Supporting evidence of preceding group A streptococcal infection; increased titer of antistreptococcal antibodies [anti-streptolysin O (ASO titers)], positive throat culture, or antigen test for group A streptococcus or recent scarlet fever.

Therapy and Prevention

Certain rheumatogenic S pyogenes strains that infect the pharynx are the cause of acute rheumatic fever and eradication of the organism from the patient’s pharynx is the first step in treating these patients. Therapy and prevention involves the following 5 steps:

Treat the group A streptococcal (S pyogenes) infection with antibiotics (i.e., penicillin or erythromycin) even if tests are negative for the organism.
Steroids and salicylates are useful in controlling the pain and inflammation associated with the polyarthritis. The nonsteroidal anti-inflammatory drug (NSAID) naproxen is effective and may be safer to use than aspirin.
If the patient has heart failure then digitalis may be required.
Patients who have had one episode of acute rheumatic fever are more likely to develop acute rheumatic fever again following a S pyogenes infection therefore chemoprophylaxis should be given to these patients. Available chemoprophylaxis regimens for those who have had acute rheumatic fever include benzathine penicillin G by intramuscular injection every month, oral penicillin V, or oral erythromycin for at least 5 years. For those who have rheumatic carditis, it is recommended to continue the prophylaxis for the entire life of the patient.
Haloperidol may help control chorea if it occurs.

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