eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Rheumatic Heart Disease

Author: Thomas K Chin, MD, Associate Professor in Pediatrics, Chief of Pediatric Cardiology, University of Tennessee College of Medicine; Consulting Staff, Department of Pediatric Cardiology, St Jude Children's Research Center
Coauthor(s): Eric M Chin, California Institute of Technology; Tariq Siddiqui, MD, Staff Physician, Department of Anesthesiology, University of Louisville Medical Center; Ann-Kristin Sundell, MD, Staff Physician, Department of Pediatrics, East Tennessee State University
Contributor Information and Disclosures

Updated: Oct 10, 2008

Introduction

Background

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.¹

Pathophysiology

Rheumatic fever develops in children and adolescents following pharyngitis with group A beta-hemolytic 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, prevents the 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-D-glucosamine 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 90 M serotypes have been identified, some of which have a long terminal antigenic domain (epitopes) similar to antigens in various components of the human heart. Rheumatogenic strains often are encapsulated mucoid strains rich in M proteins and resistant to phagocytosis. These strains are strongly immunogenic, and M-binding antibodies and T cells against the streptococcal infection may cross react with heart tissue. Streptococcal antigens that are structurally similar to those in the heart include hyaluronate in the bacterial capsule, cell wall polysaccharides (similar to glycoproteins in heart valves), and membrane antigens that share epitopes with the sarcolemma and smooth muscle.

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.

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, 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.

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. Estimations worldwide are that at least 15.6 million children and young adults have rheumatic heart disease, and 233,000 patients die from this disease each year.²

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.³

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).

Clinical

History

A diagnosis of rheumatic heart disease is made after confirming antecedent rheumatic fever. The modified Jones criteria (revised in 1992) provide guidelines for the diagnosis of rheumatic fever.⁴

• The Jones criteria require the presence of 2 major or 1 major and 2 minor criteria for the diagnosis of rheumatic fever.
  • The major diagnostic criteria include carditis, polyarthritis, chorea, subcutaneous nodules, and erythema marginatum.
  • The minor diagnostic criteria include fever, arthralgia, prolonged PR interval on ECG, elevated acute phase reactants (increased erythrocyte sedimentation rate [ESR]), presence of C-reactive protein, and leukocytosis.
• Additional evidence of previous group A streptococcal pharyngitis is required to diagnose rheumatic fever. One of the following must be present:
  • Positive throat culture or rapid streptococcal antigen test result
  • Elevated or rising streptococcal antibody titer
  • History of previous rheumatic fever or rheumatic heart disease
• These criteria are not absolute; the diagnosis of rheumatic fever can be made in a patient with chorea alone if the patient has had documented group A streptococcal pharyngitis.
• After a diagnosis of rheumatic fever is made, symptoms consistent with heart failure, such as difficulty breathing, exercise intolerance, and a rapid heart rate out of proportion to fever, may be indications of carditis and rheumatic heart disease.

Physical

Physical findings in a patient with rheumatic heart disease include cardiac and noncardiac manifestations of acute rheumatic fever. Some patients develop cardiac manifestations of chronic rheumatic heart disease.

• Cardiac manifestations of acute rheumatic fever
  • Pancarditis is the most serious and second most common complication of rheumatic fever (50%). In advanced cases, patients may complain of dyspnea, mild-to-moderate chest discomfort, pleuritic chest pain, edema, cough, or orthopnea.
  • Upon physical examination, carditis is most commonly detected by a new murmur and tachycardia out of proportion to fever. New or changing murmurs are considered necessary for a diagnosis of rheumatic valvulitis.
  • Some cardiologists have proposed that echo-Doppler evidence of mitral insufficiency, particularly in association with aortic insufficiency, may be sufficient for a diagnosis of carditis (even in the absence of accompanying auscultatory findings); however, given the sensitivity of modern Doppler devices, this remains controversial.
  • Other cardiac manifestations include congestive heart failure and pericarditis.
  • Patients in whom the diagnosis of acute rheumatic fever is made should be frequently examined because of the progressive nature of the disease.
• New or changing murmurs
  • The murmurs of acute rheumatic fever are typically due to valve insufficiency.
  • The following murmurs are most commonly observed during acute rheumatic fever:
    • Apical pansystolic murmur is a high-pitched, blowing-quality murmur of mitral regurgitation that radiates to the left axilla. The murmur is unaffected by respiration or position. Intensity varies but is grade 2/6 or greater. The mitral insufficiency is related to dysfunction of the valve, chordae, and papillary muscles.
    • Apical diastolic murmur (also known as a Carey-Coombs murmur) is heard with active carditis and accompanies severe mitral insufficiency. It is related to relative mitral stenosis, as the large volume of regurgitant flow recrosses the mitral valve during ventricular filling. It is heard best with the bell of the stethoscope, while the patient is in the left lateral position and the breath held in expiration. This murmur is low pitched, rumbling, and resembles the roll of a distant drum.
    • Basal diastolic murmur is an early diastolic murmur of aortic regurgitation and is high-pitched, blowing, decrescendo, and heard best along the right upper sternal border after deep expiration while the patient is leaning forward.
• Congestive heart failure
  • Heart failure may develop secondary to severe valve insufficiency or myocarditis.
  • The physical findings associated with heart failure include tachypnea, orthopnea, jugular venous distention, rales, hepatomegaly, a gallop rhythm, and peripheral swelling and edema.
• Pericarditis
  • A pericardial friction rub indicates that pericarditis is present.
  • Increased cardiac dullness to percussion and muffled heart sounds are consistent with pericardial effusion.
  • A paradoxical pulse (drop in systolic blood pressure with inspiration) with decreased systemic pressure and perfusion and evidence of diastolic indentation of the right ventricle on echocardiogram reflect impending pericardial tamponade. In this clinical emergency, pericardial effusion should be treated by pericardiocentesis.
• Noncardiac manifestations
  • Common noncardiac (and diagnostic) manifestations of acute rheumatic fever include polyarthritis, chorea, erythema marginatum, and subcutaneous nodules.
  • Other clinical, noncardiac manifestations include abdominal pain, arthralgias, epistaxis, fever, and rheumatic pneumonia.
    • Polyarthritis is the most common symptom and is frequently the earliest manifestation of acute rheumatic fever (70-75%). Characteristically, the arthritis begins in the large joints of the lower extremities (knees and ankles) and migrates to other large joints in the lower or upper extremities (elbows and wrists). Affected joints are painful, swollen, warm, erythematous, and limited in their range of motion. The pain is out of proportion to clinical findings. The arthritis reaches maximum severity in 12-24 hours, persists for 2-6 days (rarely more than 3 wk) at each site, and rapidly responds to aspirin. Aspirin improves symptoms in affected joints and prevents further migration of the arthritis. Polyarthritis is more common and more severe in teenagers and young adults than in younger children.
    • Sydenham chorea occurs in 10-30% of patients with rheumatic fever. Patients present with difficulty writing, involuntary grimacing, purposeless (choreiform) movements of the arms and legs, speech impairment, generalized weakness, and emotional lability. Physical findings include hyperextended joints, hypotonia, diminished deep tendon reflexes, tongue fasciculations ("bag of worms"), and a "milk sign" or relapsing grip demonstrated by alternate increases and decreases in tension when the patient grips the examiner's hand.
    • In the absence of a family history of Huntington chorea, the diagnosis of acute rheumatic fever is almost certain. A long latency period (1-6 mo) between streptococcal pharyngitis and the onset of chorea is observed; a history of an antecedent sore throat is frequently not obtained. Patients with chorea often do not demonstrate other Jones criteria. Chorea is slightly more common in females than males. It is also known as rheumatic chorea, Sydenham chorea, chorea minor, and St Vitus dance. Daily handwriting samples can be used as an indicator of progression or resolution of disease. Complete resolution of the symptoms typically occurs with improvement in 1-2 weeks and full recovery in 2-3 months. However, cases have been reported in which symptoms wax and wane for several years.
    • Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) may be associated with chorea. Children have been identified in whom group A streptococcal infection appears to have triggered a relapsing-remitting symptom complex characterized by obsessive-compulsive disorder (somatic obsessions and checking, cleaning, and repeating compulsions), and neurologic abnormalities, such as cognitive defects and motoric hyperactivity. The symptoms are prepubertal in onset and may include emotional lability, separation anxiety, and oppositional behaviors. Streptococcal infection has been proposed to trigger the formation of antibodies that cross-react with the basal ganglia of genetically susceptible hosts in a manner similar to the proposed mechanism for Sydenham chorea, thus causing the symptom complex.
    • Erythema marginatum, also known as erythema annulare, is a characteristic rash that occurs in 5-13% of patients with acute rheumatic fever. It begins as 1-3 cm in diameter, pink-to-red nonpruritic macules or papules located on the trunk and proximal limbs but never on the face. The lesions spread outward to form a serpiginous ring with erythematous raised margins and central clearing. The rash may fade and reappear within hours and is exacerbated by heat. Thus, if the lesions are not well visualized, they can be accentuated by the application of warm towels, a hot bath, or the use of tangential lighting. The rash occurs early in the course of the disease and remains long past the resolution of other symptoms. Erythema marginatum also has been reported in association with sepsis, drug reactions, and glomerulonephritis.
    • Subcutaneous nodules are currently an infrequent manifestation of rheumatic fever. The frequency has declined over the past several years to 0-8% of patients with rheumatic fever. When present, the nodules appear over the extensor surfaces of the elbows, knees, ankles, knuckles, and on the scalp and spinous processes of the lumbar and thoracic vertebrae where they are attached to the tendon sheath. They are firm, nontender, and free from attachments to the overlying skin and range in size from a few mm to 1-2 cm. They vary in number from one to dozens (mean 3-4). Histologically, they contain areas resembling the Aschoff bodies seen in the heart. Subcutaneous nodules generally occur several weeks into the disease and resolve within a month. They are strongly associated with severe rheumatic carditis, and, in the absence of carditis, the diagnosis of subcutaneous nodules should be questioned.
    • Abdominal pain usually occurs at the onset of acute rheumatic fever. This pain resembles abdominal pain from other conditions with acute microvascular mesenteric inflammation and may mimic acute appendicitis. Patients may complain of arthralgias on presentation.
    • Determine if the patient has taken aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) because these may suppress the full manifestations of the disease. Epistaxis may be associated with severe protracted rheumatic carditis. Fevers above 39°C with no characteristic pattern are initially present in almost every case of acute rheumatic fever. Fever may be low-grade in children with mild carditis or absent in patients with pure chorea. It decreases without antipyretic therapy in about 1 week, but low-grade fevers persist for 2-3 weeks. Patients with rheumatic pneumonia present with the same signs as patients with infectious pneumonia. Rheumatic pneumonia should be differentiated from respiratory distress related to congestive heart failure.
• Cardiac manifestations of chronic rheumatic heart disease: Valve deformities, thromboembolism, cardiac hemolytic anemia, and atrial arrhythmias are the most common cardiac manifestations of chronic rheumatic heart disease.
  • Valve deformities include the following:
    • Mitral stenosis occurs in 25% of patients with chronic rheumatic heart disease and in association with mitral insufficiency in another 40%. Progressive fibrosis (ie, thickening and calcification of the valve) takes place over time, resulting in enlargement of the left atrium and formation of mural thrombi in that chamber. The stenotic valve is funnel-shaped, with a "fish mouth" resemblance. Upon auscultation, S₁ is initially accentuated but becomes reduced as the leaflets thicken. P₂ becomes accentuated, and the splitting of S₂ decreases as pulmonary hypertension develops. An opening snap of the mitral valve often is heard at the apex, where a diastolic filling murmur also is heard.
    • Aortic stenosis from chronic rheumatic heart disease is typically associated with aortic insufficiency. The valve commissures and cusps become adherent and fused, and the valve orifice becomes small with a round or triangular shape. Upon auscultation, S₂ may be single because the aortic leaflets are immobile and do not produce an aortic closure sound. The systolic and diastolic murmurs of aortic valve stenosis and insufficiency are heard best at the base of the heart.
    • Thromboembolism occurs as a complication of mitral stenosis. It is more likely to occur when the left atrium is dilated, cardiac output is decreased, and the patient is in atrial fibrillation. The frequency of this complication has decreased with the use of anticoagulation and the development of surgical repair for the valve abnormality.
  • Cardiac hemolytic anemia is related to disruption of the RBCs by a deformed valve. Increased destruction and replacement of platelets also may occur.
  • Atrial arrhythmias are typically related to a chronically enlarged left atrium (from a mitral valve abnormality). Successful cardioversion of atrial fibrillation to sinus rhythm is more likely to be successful if the left atrium is not markedly enlarged, the mitral stenosis is mild, and the patient has been in atrial fibrillation for less than 6 months. Patients should be anticoagulated before cardioversion to decrease the risk of systemic embolization.

Causes

Rheumatic fever is thought to result from an inflammatory autoimmune response. Rheumatic fever only develops in children and adolescents following group A beta-hemolytic streptococcal pharyngitis, and only streptococcal infections of the pharynx initiate or reactivate rheumatic fever.  

Genetic studies show strong correlation between progression to rheumatic heart disease and human leukocyte antigen (HLA)-DR class II alleles and the inflammatory protein-encoding genes MBL2 and TNFA.²  Furthermore, both clones of heart tissue–infiltrating T cells and antibodies have been found to be cross-reactive with beta-hemolytic streptococcus. Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10-(+) cells are consistently predominant in valvular tissue, whereas IL-4 regulatory cytokine expression is consistently low.

The proposed pathophysiology for development of rheumatic heart disease is as follows: Cross-reactive antibodies bind to cardiac tissue facilitating infiltration of streptococcal-primed CD4+ T cells, which then trigger an autoimmune reaction releasing inflammatory cytokines (including TNF-alpha and IFN-gamma). Because few IL-4–producing cells are present in valvular tissue, inflammation persists, leading to valvular lesions.

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