Pediatric Rheumatic Heart Disease

Updated: Jan 03, 2017
  • Author: Thomas K Chin, MD; Chief Editor: Syamasundar Rao Patnana, MD  more...
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Overview

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]

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Pathophysiology

Rheumatic fever develops in some 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 have been shown to initiate or reactivate rheumatic fever. However, epidemiological associations in certain populations have led to speculation that group A Streptococcus impetigo could predispose to or cause rheumatic fever as well. [2] However, such a concept is contrary to earlier views advocated by well-respected authorities. [3] 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-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 120 M protein serotypes or M protein genotypes have been identifiedm [4] 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, emm typing is felt to be more discriminating than M typing. [4]

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.

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Etiology

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. [5] 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.

Decreased levels of regulatory T cells have also been associated with rheumatic heart disease and with increased severity. In utero precursors predisposing to rheumatic heart disease have also been proposed [6, 7] ; Eriksson et al suggest increased spiraling of the umbilical cord may increase risk of developing rheumatic heart disease secondary to presumed change in hemodynamic conditions during formation of the mitral valve. [8]

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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Epidemiology

United States data

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 [9] , 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. [10]

International data

In contrast to trends in the United States, the incidence of rheumatic fever and rheumatic heart disease has not substantially 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. [11]

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. [12]

Race-, sex-, and age-related demographics

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.

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

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

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Prognosis

Manifestations of acute rheumatic fever resolve over a period of 12 weeks in 80% of patients and may extend as long as 15 weeks in the remaining patients.

Rheumatic fever was the leading cause of death in people aged 5-20 years in the United States 100 years ago. At that time, the mortality rate was 8-30% from carditis and valvulitis but decreased to a 1-year mortality rate of 4% by the 1930s.

Following the development of antibiotics, the mortality rate decreased to almost 0% by the 1960s in the United States; however, it has remained 1-10% in developing countries. The development of penicillin has also affected the likelihood of developing chronic valvular disease after an episode of acute rheumatic fever. Before penicillin, 60-70% of patients developed valve disease as compared to 9-39% of patients since penicillin was developed.

In patients who develop murmurs from valve insufficiency from acute rheumatic fever, numerous factors, including the severity of the initial carditis, the presence or absence of recurrences, and the amount of time since the episode of rheumatic fever, affect the likelihood that valve abnormalities and the murmur will disappear. The type of treatment and the promptness with which treatment is initiated does not affect the likelihood of disappearance of the murmur.

In general, the incidence of residual rheumatic heart disease at 10 years is 34% in patients without recurrences but 60% in patients with recurrent rheumatic fever. Disappearance of the murmur, when it occurs, happens within 5 years in 50% of patients. Thus, significant numbers of patients experience resolution of valve abnormalities even 5-10 years after their episode of rheumatic fever. The importance of preventing recurrences of rheumatic fever is evident.

Morbidity/mortality

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.

Complications

Potential complications include heart failure from valve insufficiency (acute rheumatic carditis) or stenosis (chronic rheumatic carditis). Associated cardiac complications include atrial arrhythmias, pulmonary edema, recurrent pulmonary emboli, infective endocarditis, intracardiac thrombus formation, and systemic emboli.

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