Pediatric Rheumatic Heart Disease

Updated: Dec 01, 2019
  • Author: Thomas K Chin, MD; Chief Editor: Syamasundar Rao Patnana, MD  more...
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Rheumatic heart disease is the most serious complication of rheumatic fever. Acute rheumatic fever and rheumatic heart disease are thought to result from an autoimmune response, but the exact pathogenesis remains unclear. Rheumatic heart disease is the result of permanent heart valve damage secondary to acute rheumatic fever and the resultant rheumatic carditis involving pericarditis, myocarditis, or valvulitis. With chronic rheumatic heart disease, patients develop mitral valve stenosis with varying degrees of regurgitation, atrial dilatation, arrhythmias, and ventricular dysfunction. Although the mitral valve is involved in most cases of rheumatic heart disease, the aortic and tricuspid valves can be involved as well. A comprehensive resource provided by the World Health Organization (WHO) addresses the diagnosis and treatment of rheumatic fever and rheumatic heart disease. [1, 2]

At this time, rheumatic fever is uncommon among children in the United States. In contrast, the incidence of rheumatic fever and rheumatic heart disease in developing countries has not substantially decreased.

A diagnosis of rheumatic heart disease is made after confirming antecedent rheumatic fever. Acute rheumatic fever is a systemic disease, thus, patients may present with a large variety of symptoms. The modified Jones criteria provide guidelines for making the diagnosis of rheumatic fever, which requires the presence of either two major or one major and two minor criteria. For recurrent rheumatic fever, the requirement is for two major, one major and two minor, or three minor criteria. Evidence of previous group A streptococcal pharyngitis is required to diagnose rheumatic fever.

  • The  major diagnostic criteria: Carditis, polyarthritis, chorea, subcutaneous nodules, erythema marginatum
  • The  minor diagnostic criteria: Fever, polyarthralgia, prolonged PR interval, elevated peak erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP)

Cardiac manifestations of acute rheumatic fever include pancarditis, as evidenced by a new or changing murmur or via echocardiography. Treatment involves the initiation of secondary prophylaxis against group A beta-hemolytic streptococcal infection and management of clinical sequelae including heart failure.

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.



Rheumatic fever develops in some children and adolescents following pharyngitis with group A beta-hemolytic Streptococcus (ie, Streptococcus pyogenes or GABHS). 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 a small percentage 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, epidemiologic associations in certain populations have led to speculation that group A Streptococcus (GAS) impetigo could predispose to or cause rheumatic fever as well. [3] However, such a concept is contrary to earlier views advocated by well-respected authorities. [4]  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 such as rheumatic fever.

GAS 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. GAS elaborate the cytolytic toxins streptolysins S and O. Of these two toxins, streptolysin O induces persistently high antibody titers that provide a useful marker of GAS infection and its nonsuppurative complications. Relatively recent studies using enzyme-linked immunosorbent assays have shown a correlation between anti-streptolysin O and anti-human cardiac myosin antibodies. [5]

GAS, 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. GAS 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 GAS infection in humans. More than 240 M protein serotypes or M protein genotypes have been identified, [6]  some of which have a long terminal antigenic domain (ie, epitopes) similar to antigens in various components of the human heart. Certain serotypes have demonstrated an association with rheumatic fever, but a specific factor is yet to be identified. [6]

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. [6]

At least some rheumatogenic strains of GAS have antigenic domains similar to antigens in components of the human heart, and some authors have proposed that anti-M antibodies against the streptococci may cross-react with heart tissue, causing the pancarditis that is observed in rheumatic fever. So-called molecular mimicry between streptococcal and human proteins is believed to involve both the B and T cells of peripheral blood, with infiltration of the heart by T cells. Some authors believe that an increased production of inflammatory cytokines is the final mechanism of the autoimmune reaction that causes damage to cardiac tissue in rheumatic heart disease. An insufficiency of interleukin-4 (IL-4)-producing cells in the valve tissue may also contribute to the valve lesions. Streptococcal antigens, which 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. 

Rheumatic fever is thought to result from an inflammatory autoimmune response. Rheumatic fever only develops in children and adolescents following GABHS pharyngitis, and only streptococcal infections of the pharynx initiate or reactivate rheumatic fever. 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 tumor necrosis factor [TNF]-alpha and interferon [IFN]-gamma). Because few IL-4–producing cells are present in valvular tissue, inflammation persists, leading to valvular lesions. Some studies have suggested that various cardiac defects linked with rheumatic heart disease have specific antibodies associated with them. In females with isolated mitral regurgitation, anticardiolipin (ACL) antibodies are present. In both males and females with mixed valvular heart disease, anti-endothelial cell antibodies (AECA) are present. [7]

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 in most cases of rheumatic heart disease, followed by the aortic valve (20%-30%). [1] The tricuspid valve is also commonly affected; however, disease is often subclinical. The pulmonary valve is rarely affected. Severe valve insufficiency during the acute phase may result in congestive heart failure and even death (10%). A larger proportion can develop subclinical carditis that is detected only on echocardiography (53%). [8]  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. [9]

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. Most often, heart failure is the presenting complication seen in endemic areas (33%). [10]  Other complications include atrial fibrillation, pulmonary hypertension, and cardioembolic stroke. 

Genetic studies show a 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. [11]  Genetic testing evaluating the mannose-binding lectin 2 (MBL2) gene has demonstrated an increased risk of rheumatic heart disease in patients with genotypes that result in higher production of mannose-binding lectin. [12]  Furthermore, both clones of heart tissue–infiltrating T cells and antibodies have been found to be cross-reactive with beta-hemolytic streptococcus. IFN-gamma, TNF-alpha, and 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 [13, 14] ; Eriksson et al have suggested that increased spiraling of the umbilical cord may increase the risk of developing rheumatic heart disease secondary to presumed change in hemodynamic conditions during formation of the mitral valve. [15]

New data are consistently published regarding further understanding of the pathophysiology of rheumatic heart disease. Studies have shown evidence of right ventricular apoptosis in patients with valvular heart disease in the setting of rheumatic fever; this was noted to occur early in the disease course even in subjects with lower right ventricular systolic pressures. [16]  A separate study demonstrated the role of a polycomb complex protein and transcription activator in regulating cardiac stem cell proliferation during acute, but not chronic, rheumatic heart disease. [17] Specific microRNAs have been identified that have significant downregulation in children with rheumatic heart disease. [18]  Moreover, microRNA sequencing has revealed that IL-1β and IL-1 receptor 1 are involved in rheumatic heart disease, further demonstrating the significance of the inflammatory process in this condition. [19]



United States data

As noted earlier, rheumatic fever is currently uncommon among children in the United States: The incidence of rheumatic fever and rheumatic heart disease has decreased in the United States and other industrialized countries in the past 80 years. The prevalence of rheumatic heart disease in the United States at present is less than 0.05 per 1000 population, with rare regional outbreaks reported in Tennessee in the 1960s and in Utah, [20]  Ohio, and Pennsylvania in the 1980s. In contrast, in the early 1900s, the incidence of rheumatic heart disease was reportedly 5-10 cases per 1000 population. The decreased incidence of rheumatic fever has been attributed to the introduction of penicillin or to a change in the virulence of Streptococcus.

The incidence of acute rheumatic fever in other developed countries, such as Italy, is comparable to that of the United States. [21]  However, a 2016 assessment of temporal trends of patients diagnosed with acute rheumatic fever in the United States from 2001 to 2011 showed that since 2001, national acute rheumatic fever admissions have steadily increased, with a peak in 2005 and a reduction afterward. [22]  Within the United States, the prevalence is greatest in the South (34.32%) compared to the Northeast (25.05%), Midwest (22.95%), and West (17.69%). [22]

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 rheumatic heart disease, with 282,000 new cases and 233,000 deaths from this disease each year. [23]

Worldwide, the mean incidence of acute rheumatic fever is 19 per 100,000, with higher incidence rates in Eastern Europe, the Middle East, Asia, and Australia. [24]  Specific to rheumatic heart disease, a 2017 report of 2015 data found that the age-standardized prevalence was 444 per 100,000 in countries with an endemic pattern and 3.4 per 100,000 in countries with a nonendemic pattern. [25]  The 2013 Global Burden of Disease Study demonstrated a drop in the age-standardized death rate for rheumatic heart disease of 55% from 1990 to 2013 (9.8/100,000 in 1990 to 4.4/100,000 in 2013). [26, 27]

Race-related data

Native Hawaiian and Maori children (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. [27]  In 2015, 73% of global cases of rheumatic heart disease were accounted for in India, China, Pakistan, Indonesia, and the Democratic Republic of the Congo, [25]  highlighting the fact that rheumatic heart disease continues to be a significant problem for developing countries. A 2019 Brazilian public health study demonstrated six major categories of issues for which underserved patients must overcome to prevent and treat rheumatic heart disease: the effects of living in a slum, barriers to access and utilization of primary healthcare services, treatment in primary healthcare services, access/utilization of specialized healthcare services, treatment in specialized healthcare services, and certain systemic issues. [28]  

Within the United States, black individuals have the highest mortality (5.00%) compared to white persons (3.01%), Hispanic patients (1.66%) and Asian populations (0.89%). As median income decreases, the frequency of rheumatic fever increases, with patients earning less than $25,000 per year making up 23.74% of admissions. [22]

Sex- and age-related demographics

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. However, group A beta-hemolytic streptococcal (GABHS) pharyngitis is uncommon in children younger than 3 years, and acute rheumatic fever is extremely rare in this age group in industrialized countries. Although rheumatic fever is less commonly seen in adults relative to children, it accounts for 20% of adult cases.



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. 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, and the importance of preventing recurrences of rheumatic fever is evident. The development of penicillin has also affected the likelihood of developing chronic valvular disease after an episode of acute rheumatic fever. Before the advent of penicillin, 60%-70% of patients developed valve disease as compared to 9%-39% of patients since penicillin.

In patients who develop murmurs from valve insufficiency following 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 do not affect the likelihood of disappearance of the murmur.

Rheumatic fever was the leading cause of death in people aged 5-20 years in the United States 100 years ago. At that time, mortality was 8%-30% from carditis and valvulitis, but this decreased to a 1-year mortality of 4% by the 1930s. Following the development of antibiotics, US mortality fell to almost 0% by the 1960s; however, it has remained 1%-10% in developing countries.

Rheumatic heart disease is the major cause of morbidity from rheumatic fever, and it is the major cause of mitral insufficiency and stenosis in the United States and the world. The number of previous attacks of rheumatic fever, the length of time between the disease onset and initiation of therapy, and the patient's sex are variables that correlate with the severity of the valve disease. Insufficiency due to acute rheumatic valve disease resolves in 70%-80% of patients if they adhere to antibiotic prophylaxis.


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.


Patient Education

Timely evaluation and treatment of pharyngitis in children to helps prevent rheumatic fever. Emphasize the importance of prophylaxis against recurrent streptococcal pharyngitis and rheumatic fever with each patient.

Secondary prophylaxis of patients with previous rheumatic fever and valve involvement with the administration penicillin injections every 3-4 weeks decreases the recurrence of rheumatic heart disease.