Pediatric Rheumatic Heart Disease


Background

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. [12]

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.

Pathophysiology

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. [3However, 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%). [1The 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 [1314; 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. [17Specific 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]

Epidemiology

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). [2627]

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.

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. 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.

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.

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.

CLINICAL PRESENTATION


History

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.

Many patients present with history of sore throat 1-5 weeks prior to disease onset (70% of older children and young adults). However, only 20% of younger children can recall an antecedent sore throat.

Other symptoms at time of presentation can include fever, rash, headache, weight loss, epistaxis, fatigue, malaise, diaphoresis, and pallor. Further symptoms can include chest pain with orthopenea, abdominal pain, and vomiting.

The patient history can also suggest symptoms more specific for rheumatic fever, such as the following:

  • Migratory joint pain
  • Nodules under the skin
  • Increased irritability, shortened attention span, personality changes
  • Motor dysfunction

Patients with a history of rheumatic fever are at high risk of recurrence. The highest risk of recurrence occurs within 5 years of the initial episode. The younger the patient at the time of the initial episode, the higher the risk of recurrence. Typically, recurrence of acute rheumatic fever is similar to the initial attack, however, the risk of carditis and severity of valvular damage worsens with each attack.

Diagnostic criteria

The modified Jones criteria, revised in 1992 and again in 2016, provide guidelines for making the diagnosis of rheumatic fever  [29. The newest update to the Jones criteria differentiates between low risk populations and moderate to high risk populations. Low risk populations are defined as an incidence of acute rheumatic fever in less than 2/100,000 school-aged children or all-age rheumatic heart disease prevalence of less than 1/1000 population per year. Moderate to high risk populations were defined as groups experiencing an incidence of 153-380/100,000 cases per year in the 5-14 year old age group. [29 The new criteria also include a role for echocardiography in addition to a clinical assessment of the heart for a diagnosis of carditis. These new guidelines are in closer alignment with other international guidelines such as those from the World Health Association.

For rheumatic fever,  the requirement is for 2 major or 1 major and 2 minor criteria

For recurrent rheumatic fever , the requirement is for 2 major, 1 major and 2 minor, or 3 minor criteria.

Evidence of previous group A streptococcal pharyngitis is necessary. Exceptions to this requirement can be made in patients with chorea and clinical or subclinical (echo diagnosis) evidence of carditis. Specific to recurrence of rheumatic fever, when minor manifestations alone are present, the exclusion of other more likely causes of the clinical presentation is recommended before diagnosing recurrent rheumatic fever.

The major diagnostic criteria:

  • Carditis and valvulitis: Clinical and/or subclinical (echo) (50-70%)
  • Polyarthritis: Typically a migratory polyarthritis primarily involving the large joints (35-66%)
    • Monoarthritis or polyarthralgia are adequate to achieve a major diagnostic criteria in moderate/high risk population
    • For polyarthraliga, exclusion of other more likely diagnosis is required
  • Chorea (10-30%)
  • Subcutaneous nodules (0-10%)
  • Erythema marginatum (< 6%)

The minor diagnostic criteria:

  • Fever ≥38.5°C
    • Fever ≥38°C to achieve a minor diagnostic criteria in moderate/high risk populations
  • Polyarthralgia
    • Monoarthralgia is adequate to achieve a minor diagnostic criteria in moderate/high risk populations
  • Prolonged PR interval for age on electrocardiography
  • Elevated peak erythrocyte sedimentation rate during acute illness ≥60mm/h and/or C-reactive protein ≥3.0mg/dL

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 (anti-streptolysin O titer or anti-DNAseB)

There are some notable exceptions to strict adherence to the Jones criteria. 

  • Chorea: This may occur late and be the only manifestation of rheumatic fever. Given this, it may be impossible to document previous group A strep pharyngitis.
  • Indolent Carditis: Patients who present late to medical attention months after the onset of rheumatic fever may have insufficient support to fulfill the criteria.
  • Newly ill patients with a history of rheumatic fever: Distinguishing recurrent carditis from pre-existing significant rheumatic heart disease may be impossible. This is especially true for patients with history of rheumatic heart disease who have supporting evidence of a recent GAS infection and who manifest either a single major or several minor criteria.

After a diagnosis of rheumatic fever is made, symptoms consistent with heart failure, such as difficulty breathing, exercise intolerance, and rapid heart rate out of proportion to fever may be indications of carditis and rheumatic heart disease.

Physical Examination

Physical findings in a patient with rheumatic heart disease include cardiac and noncardiac manifestations of acute rheumatic fever. Some patients go on to 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. For a graph illustrating the time course for the carditis relative to the other clinical manifestations of rheumatic fever, see the Medscape Reference article Pediatric Rheumatic Fever.

New or changing murmurs are considered necessary for a diagnosis of rheumatic valvulitis. Upon physical examination, carditis is most commonly detected by a new murmur and tachycardia out of proportion to fever. The murmurs of acute rheumatic fever are from valve regurgitation/insufficiency and the murmurs of chronic rheumatic fever are from valve stenosis. Some cardiologists have proposed that echocardiographic 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) [30; however, given the sensitivity of modern doppler devices, this remains controversial.

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. The mechanism for this murmur is postulated to be due to mitral valvulitis, relative mitral stenosis, as the large volume of regurgitant flow traverses the mitral valve during ventricular filling, or combination thereof. 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.

  • Basal diastolic murmur is an early diastolic murmur of aortic regurgitation and is high-pitched, blowing, decrescendo, and heard best along the right upper and mid-left sternal border after deep expiration while the patient is leaning forward.

Congestive 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, edema and swelling of the peripheral extremities.

Pericarditis can be demonstrated by the presence of a pericardial friction rub on exam. Increased cardiac dullness to percussion and muffled heart sounds are consistent with pericardial effusion. A paradoxical pulse (and accentuated fall 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. Confirm this clinical emergency with ECG, and evacuate the effusion by pericardiocentesis if it is producing hemodynamic compromise.

Noncardiac manifestations of acute rheumatic fever

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 upper (elbows and wrists) or lower extremities. 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 weeks) at each site. Aspirin rapidly improves symptoms in affected joints and prevents further migration of arthritis. Polyarthritis is more common and more severe in teenagers and young adults than in younger children. Patients suffering multiple attacks may exhibit destructive arthritis (Jaccoud arthritis).

Chorea,​ also known as rheumatic chorea, Syndenham chorea, chorea minor, and St. Vitus dance occurs in 10-30% of patients with rheumatic fever. This is slightly more common in females than it is in males. 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 in patients with chorea. A long latency period of 1 to 6 months between streptococcal pharyngitis and the onset of chorea is observed. Given this, a history of an antecedent sore throat is frequently not obtained. In addition, patients with chorea often do not demonstrate other Jones criteria.
  • 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. Patients with Syndenham chorea and obsessive-compulsive symptoms tend to show aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions. Neurologic abnormalities, such as cognitive defects and motoric hyperactivity can also occurs. 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 1-3cm 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. For an example of the typical rash of erythema marginatum, see the Medscape Reference article Pediatric Rheumatic Fever.

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. These nodules are strongly associated with severe rheumatic carditis, and, in the absence of carditis, the diagnosis of subcutaneous nodules should be questioned.

Other clinical, noncardiac manifestations include abdominal pain, arthralgia, epistaxis, [31 fever, and rheumatic pneumonia.

  • 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.
  • Arthralgias can be reported upon presentation. It is important to determine if the patient has been taking nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin because these may suppress the full manifestations of the disease. Arthralgias cannot be considered a minor manifestation if arthritis is present.
  • 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 (38-38.5°C) in children with mild carditis or absent in patients with pure chorea. Fevers decrease without antipyretic therapy in about 1 week, but low-grade fevers persist for 2-3 weeks.
  • Rheumatic pneumonia presents 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

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 and balloon valvuloplasty techniques for addressing the valve abnormality.

Cardiac hemolytic anemia is related to disruption of the red blood cells 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

DDx


Diagnostic Considerations

 

 

Differential Diagnoses

Workup

Approach Considerations

The incidence of rheumatic heart disease, the facilities available for identifying and treating the illness, and physician training and experience with this disorder all vary widely with geographic location. Furthermore, scientific understanding of rheumatic heart disease remains incomplete. For these reasons, recommending a fixed set of guidelines that apply to all situations with respect to the diagnostic approach for rheumatic heart disease is difficult.

Laboratory Studies

Testing indicated in patients with acute rheumatic fever is outlined in this section.

Throat culture

Appropriate technique for throat culture collection includes vigorous swabbing of both tonsils and the posterior orpharynx. The sample is grown on sheep blood agar to demonstrate the presence of beta-hemolytic streptococci infection. Colonies that grow on this agar can then be tested with latex agglutination, fluorescent antibody assay, coagglutination, or precipitation techniques to demonstrate group A beta hemolytic streptococci (GABHS) infection.

Note: Throat culture findings for GABHS are usually negative by the time symptoms of rheumatic fever or rheumatic heart disease appear.

Attempt to isolate the organism before the initiation of antibiotic therapy to help confirm a diagnosis of streptococcal pharyngitis and to allow typing of the organism if it is isolated successfully.

Rapid antigen detection test (RADT)

RADT allows for rapid detection of group A streptococcal (GAS) antigen as well as for rapid diagnosis of streptococcal pharyngitis and the initiation of antibiotic therapy while the patient is still in the physician's office.

Because RADT has a specificity of greater than 95% but a sensitivity of only 60-90%, a throat culture should be obtained in conjunction with this test.

Anti-streptococcal antibodies

The clinical features of rheumatic fever begin at the time antistreptococcal antibody levels are at their peak. Thus, antistreptococcal antibody testing is useful for confirming previous GAS infection. The elevated level of antistreptococcal antibodies is useful, particularly in patients that present with chorea as the only diagnostic criterion.

Sensitivity for recent infections can be improved by testing for several antibodies. Antibody titers should be checked at 2-week intervals to detect a rising titer.

The most common extracellular anti-streptococcal antibodies tested include antistreptolysin O (ASO), anti-deoxyribonuclease (DNAse) B, anti-hyaluronidase, anti-streptokinase, anti-streptococcal esterase, and anti-nicotinamide adenine dinucleotide (anti-NAD). Antibody tests for cellular components of GAS antigens include anti-streptococcal polysaccharide, anti-teichoic acid antibody, and anti–M protein antibody.

In general, the ratio of antibodies to extracellular streptococcal antigens rises during the first month after infection and then plateaus for 3-6 months before returning to normal levels after 6-12 months. When the ASO titer peaks (2-3 weeks after the onset of rheumatic fever), the sensitivity of this test is 80%-85%.

The anti-DNAse B has a slightly higher sensitivity (90%) for detecting rheumatic fever or acute glomerulonephritis than ASO titers. Anti-hyaluronidase results are frequently abnormal in rheumatic fever patients with a normal level of ASO titer and may rise earlier and persist longer than elevated ASO titers during rheumatic fever.

Acute phase reactants

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in rheumatic fever due to the inflammatory nature of the disease. Both tests have a high sensitivity but low specificity for rheumatic fever. They may be used to monitor the resolution of inflammation, detect relapse when weaning from aspirin, or identify the recurrence of disease.

Specifically, elevated mean plasma high-sensitive CRP has been shown to have an association with rheumatic heart disease. [32]

Heart-reactive antibodies

Tropomyosin levels are elevated in acute rheumatic fever.

Rapid detection test for D8/17

This immunofluorescence technique for identifying the B-cell marker D8/17 is positive in 90% of patients with rheumatic fever. It may be useful for identifying patients who are at risk for developing rheumatic fever.

Ongoing investigations

Current research is being pursued to evaluate for new diagnostic and prognostic markers in rheumatic heart disease. In subjects with rheumatic heart disease requiring percutaneous balloon mitral valvotomy, N-terminal (NT)-pro b-type natriuretic peptide (BNP) (NT-proBNP) levels correlated with improvements in left atrial function seen after the procedure. [33 Another marker that has demonstrated elevation in rheumatic heart disease is procollagen type 1 C-peptide and interleukin (IL)-6 concentration. [34]

Lower vitamin D levels, specifically 25-hydroxyvitamin D, have been shown to correlate with more severely damaged and calcified valves in rheumatic heart disease. It has been hypothesized that the role of vitamin D as an immunomodulator may have an impact on the severity of autoimmune valve damage in rheumatic heart disease. [35]

Electrocardiography

On electrocardiography (ECG), sinus tachycardia most frequently accompanies acute rheumatic heart disease. Alternatively, some children develop sinus bradycardia from increased vagal tone. However, no correlation between bradycardia and the severity of the carditis is noted.

First-degree atrioventricular (AV) block (prolongation of the PR interval) is observed in some patients with rheumatic heart disease. This abnormality may be related to localized myocardial inflammation involving the AV node or to vasculitis involving the AV nodal artery. First-degree AV block is a nonspecific finding and should not be used as a criterion for the diagnosis of rheumatic heart disease. Its presence does not correlate with the development of chronic rheumatic heart disease.

Second-degree (intermittent) and third-degree (complete) AV block with progression to ventricular standstill have been described. Heart block in the setting of rheumatic fever, however, typically resolves with the rest of the disease process.

When acute rheumatic fever is associated with pericarditis, ST-segment elevation may be present and is most marked in leads II, III, aVF, and V4 -V6.

Patients with rheumatic heart disease also may develop atrial flutter, multifocal atrial tachycardia, or atrial fibrillation from chronic mitral valve disease and atrial dilatation. Left atrial enlargement may be seen in patients with mitral stenosis. Left ventricular hypertrophy may be observed in patients with significant mitral insufficiency or aortic insufficiency.

Imaging Studies

Chest radiography

Cardiomegaly, pulmonary congestion, and other findings consistent with heart failure may be seen on chest radiography in patients with rheumatic heart disease.

When the patient has fever and respiratory distress, chest radiography helps to differentiate heart failure from rheumatic pneumonia.

Doppler echocardiography

The World Heart Federation has published guidelines for identifying individuals with rheumatic heart disease who don't have a clear history of acute rheumatic fever. Based on two-dimensional (2D) imaging and pulsed and color Doppler interrogation, patients are divided into the following three categories:

  • Definite rheumatic heart disease
  • ​Borderline rheumatic heart disease
  • Normal

For pediatric patients (defined as age < 20 years), definite echocardiographic features include pathologic mitral regurgitation (MR) and at least two morphologic features of: rheumatic heart disease of the mitral valve, a mitral stenosis mean gradient of more than 4 mmHg, pathologic aortic regurgitation, and at least two morphologic features of rheumatic heart disease of the aortic valve, or borderline disease of both the aortic valve and mitral valve. [36]

The revised American Heart Association criteria align more closely with the World Heart Federation guidelines above. In the most recent version of the revised Jones criteria, morphologic and Doppler findings on echocardiography may supersede ausculatory findings for carditis. Studies in Cambodia and Mozambique demonstrated a 10-fold increase in the prevalence of rheumatic heart disease when echocardiography was used for clinical screening compared with strictly clinical findings. [37]

Acute morphologic changes in the mitral valve may include annular dilatation, chordal elongation, chordal rupture resulting in flail leaflet with severe mitral regurgitation, or prolapse/beading/nodularity of the leaflet tips. Doppler findings should demonstrate regurgitation in at least two views, with a pansystolic jet in at least one view. Chronic changes in the mitral valve show leaflet thickening and calcification, with restricted motion. There may also be evidence of chordal thickening and fusion. Changes in the aortic valve may include prolapse, coaptation defect, and thickening of the leaflets with restricted motion. Doppler findings should demonstrate regurgitation in at least two views, with a pansystolic jet in at least one view. [29 

Acute rheumatic heart disease

  • ​Doppler echocardiography identifies and quantitates valve insufficiency and ventricular dysfunction.
  • During acute rheumatic fever, the left ventricle is frequently dilated in association with a normal or increased fractional shortening. Thus, some cardiologists believe that valve insufficiency (from endocarditis), rather than myocardial dysfunction (from myocarditis), is the dominant cause of heart failure in acute rheumatic fever.
  • With mild carditis, Doppler evidence of mitral regurgitation may be present during the acute phase of disease but resolves in weeks to months. In contrast, patients with moderate-to-severe carditis have persistent mitral and/or aortic regurgitation. The most important echocardiographic features of mitral regurgitation from acute rheumatic valvulitis are annular dilatation, elongation of the chordae to the anterior leaflet, and a posterolaterally directed mitral regurgitation jet.

Chronic rheumatic heart disease

  • Echocardiography may be used to track the progression of valve stenosis and may help to determine the time for surgical intervention.
  • The leaflets of affected valves become diffusely thickened, with fusion of the commissures and chordae tendineae.
  • Increased echodensity of the mitral valve may signify calcification.

Simplified echocardiographic screening with handheld echocardiography

  • A 2019 study suggests that simplified echocardiographic screening criteria are highly accurate in the recognition and risk stratification of rheumatic heart disease. [38]
  • An investigation of handheld echocardiography as a screening tool in Ugandan children found it to be 90% sensitive and 92% specific for identifying rheumatic heart disease. [39]
  • A study by Godown et al that assessed the value of handheld echocardiography over auscultation to identify rheumatic heart disease demonstrated that auscultation alone was a poor screening test for rheumatic heart disease and that handheld echocardiography significantly improved detection of rheumatic heart disease. [40 This study also showed that handheld echocardiography was a cost-effective screening strategy for rheumatic heart disease in resource-limited settings.

The image below depicts the typical systolic mitral insufficiency jet observed with rheumatic heart disease.

Pediatric rheumatic heart disease. This parasternaPediatric rheumatic heart disease. This parasternal long-axis echocardiographic view demonstrates the typical systolic mitral insufficiency jet observed with rheumatic heart disease (blue jet extending from the left ventricle [LV] into the left atrium [LA]). The jet is typically directed to the lateral and posterior wall. Ao = aorta; RV = right ventricle.

The image below depicts the typical diastolic aortic insufficiency jet observed with rheumatic heart disease.

Pediatric rheumatic heart disease. This parasternaPediatric rheumatic heart disease. This parasternal long-axis echocardiographic view demonstrates the typical systolic mitral insufficiency jet observed with rheumatic heart disease (blue jet extending from the left ventricle [LV] into the left atrium [LA]). The jet is typically directed to the lateral and posterior wall. Ao = aorta; RV = right ventricle.

Cardiac magnetic resonance imaging (CMR)

The use of CMR in rheumatic heart disease is still being investigated

Studies have demonstrated that CMR may be superior to echocardiography in obtaining information about myocardial fibrosis. Other advantages of CMR include that this imaging modality is not operator dependent nor dependent on acoustic windows. One of the major drawbacks to CMR however, is that this type of study is often not available in endemic areas. Other limitations include the inability to perform this testing on anyone with metallic implants of any nature. [41]

Histologic Findings

Pathologic examination of the insufficient valves in patients with rheumatic heart disease may reveal verrucous lesions at the line of closure.

Aschoff bodies (perivascular foci of eosinophilic collagen surrounded by lymphocytes, plasma cells, and macrophages) are found in the pericardium, perivascular regions of the myocardium, and endocardium. The Aschoff bodies assume a granulomatous appearance with a central fibrinoid focus and are eventually replaced by nodules of scar tissue. Anitschkow cells are plump macrophages within Aschoff bodies.

In the pericardium, fibrinous and serofibrinous exudates may produce an appearance of "bread and butter" pericarditis.

Procedures

Cardiac catheterization

Cardiac catheterization is not indicated in acute rheumatic heart disease. However, with chronic disease, heart catheterization has been performed to evaluate mitral and aortic valve disease. This procedure is also performed in preparation for balloon valvuloplasty of the stenotic mitral valves if indicated.

Postcatheterization precautions include hemorrhage, pain, nausea, vomiting, and arterial or venous obstruction from thrombosis or spasm. Complications may include mitral insufficiency after balloon dilation of the mitral valve, tachyarrhythmias, bradyarrhythmias, and vascular occlusion.

TREATMENT AND MANAGEMENT


Medical Care

As of 2007, the American Heart Association no longer recommends subacute bacterial endocardial prophylaxis in patients with aortic or mitral valve abnormalities secondary to rheumatic heart disease. [4243]

Medical therapy in rheumatic heart disease includes attempts to prevent rheumatic fever and, thus, rheumatic heart disease. In patients who develop rheumatic heart disease, therapy is directed toward eliminating the group A streptococcal (GAS) pharyngitis if still present and providing supportive treatment for congestive heart failure. Following resolution of the acute episode, subsequent therapy is directed toward preventing recurrent rheumatic heart disease in children and monitoring for the complications and sequelae of chronic rheumatic heart disease in adults.

Prevention of rheumatic fever in patients with group A beta hemolytic streptococci (GABHS) pharyngitis

Patients who have positive rapid-antigen testing or throat culture for GAS in the setting of symptomatic pharyngitis should be treated with appropriate antibiotics. For patients with GABHS pharyngitis, a meta-analysis supports a protective effect against rheumatic fever when penicillin is used following the diagnosis. [44]

At this time, oral (PO) penicillin V (250 mg twice [BID] or thrice daily [TID] if < 27 kg and 500 mg BID or TID if >27 kg) is the drug of choice for treatment of GABHS pharyngitis. Amoxicillin (50 mg/kg/day; maximum of 1000 mg/day) is an acceptable alternative and has the benefit of once-daily dosing. Another option is a single dose of intramuscular (IM) benzathine penicillin G (0.6 million units if < 27 kg or 1.2 million units if >27 kg) or a benzathine/procaine penicillin combination. This option ensures adherence, and because the noncompliance rates for 10 days of PO penicillin are high, some clinicians recommend this choice. Furthermore, benzathine penicillin G is the only drug studied for the prevention of acute rheumatic fever.

For patients with a mild penicillin allergy, cephalosporins can be used, typically given for a 10-day course, and demonstrate a high efficacy rate. Options include cephalexin, cefuroxime, cefpodoxime, and cefdinir. In children with more severe reactions to penicillin, including anaphylaxis or other immunoglobulin (Ig)E-mediated reaction, macrolides (azithromycin for a 5-day course or clarithromycin for a 10-day course) can be used. In instances of severe reaction to penicillins where there is concominant concern for macrolide resistance, clindamycin (10-day course) is another alternative therapy. Do not use tetracyclines or sulfonamides to treat GABHS pharyngitis.

For recurrent GAS pharyngitis, a detailed history will help to guide further management. Other etiologies such as alternative bacterial sources and viruses should be considered. Generally, a second, repeat 10-day course of the same antibiotic may be used. If the cause of symptoms is suspected to be due to treatment failure from noncompliance, the single IM injection of benzathine penicillin G may be a good option. If choosing an alternative antibiotic, one with improved beta-lactamase activity relative to the original antibiotic is preferred, such as amoxicillin-clavulanate or a later-generation cephalosporin. 

Control measures for patients with GABHS pharyngitis

  • Hospitalized patients: Place hospitalized patients with GABHS pharyngitis or pneumonia on droplet precautions, as well as standard precautions, until 24 hours after the initiation of appropriate antibiotics.
  • Exposed persons: People in contact with patients having documented cases of streptococcal infection first should undergo appropriate laboratory testing if they have clinical evidence of GABHS infection; if infected, these individuals should undergo antibiotic therapy.
  • School and childcare centers: Children with GABHS infection should not attend school or childcare centers for the first 24 hours after the initiation of antimicrobial therapy.

Chronic carriers of GABHS

In general, animicrobal therapy is is not indicated in chronic GABHS carriers. These patients are unlikely to develop complications, specifically acute rheumatic fever. [45 Exceptions to this include the following:

  • Outbreaks of rheumatic fever or poststreptococcal glomerulonephritis
  • Family history of rheumatic fever
  • During outbreaks of GAS pharyngitis in a closed community or when multiple episodes of documented GABHS pharyngitis occur within a family despite appropriate therapy
  • When tonsillectomy is considered for chronic GABHS carriage
  • Following GAS toxic shock syndrome or necrotizing fasciitis in a household contact
  • GABHS carriage is difficult to eradicate. Options include clindamycin, amoxicillin-clavulanate, and penicillin + rifampin (rifampin given only last 4 days of therapy).

Treatment for patients with rheumatic fever and rheumatic heart disease

Therapy is directed toward eliminating the GABHS pharyngitis (if still present) and providing supportive treatment of congestive heart failure.

Treat residual GABHS pharyngitis as outlined above, if still present.

Previously, treatment of the acute inflammatory manifestations of acute rheumatic fever included salicylates, nonsteroidal anti-inflammatory agents (NSAIDs), steroids, and intravenous immunoglobulin (IVIG). However, current data do not show improved cardiac outcomes with the use of these interventions. [46 Thus, these agents are not recommended for the treatment of carditis associated with acute rheumatic fever. However, some of these agents may be of benefit for the arthritis associated with acute rheumatric fever.

In certain instances of severe carditis associated with acute rheumatic fever, glucocorticoids such as prednisone (1-2 mg/kg/day with a maximum of 80 mg) can be used. Oftentimes, these patients have extremely elevated inflammatory markers. Typically, if a patient is also taking aspirin or other NSAIDs, these medications are stopped once glucocorticoids are initiated and then resumed once the course is completed. It is always important to remember to gradually taper the steroid dose if needed for a prolonged period to prevent adrenal insufficiency. 

Patients with heart failure due to acute rheumatic fever should be treated appropriately. Include the use of digoxin and diuretics, afterload reduction, supplemental oxygen, bed rest, and sodium and fluid restriction.

Loop diuretics (furosemide) are the most commonly used diuretics in children. Thiazide diuretics such as chlorothiazide can be used in conjunction with loop diuretics. Spironolactone (a mineralocorticoid receptor antagonist) can also be added for further diuresis, specifically in patients with hypokalemia. 

Afterload reduction with an agent such as an angiotensin-converting enzyme (ACE)-inhibitor may be effective in improving cardiac output, particularly in the presence of mitral and aortic insufficiency. Start these agents judiciously: Use a small, initial test dose (some patients have an abnormally large response to these agents), and administer them only after correcting hypovolemia. Angiotensin-receptor blockers (ARBs) are an alternative to ACE-inhibitors in patients who cannot tolerate them; however, data are limited in the pediatric population for this class of medication.

When heart failure persists or progresses during an episode of acute rheumatic fever in spite of aggressive medical therapy, surgery is indicated and may be life-saving for severe mitral and/or aortic insufficiency.

Prophylaxis for patients following rheumatic heart disease)

Preventive and prophylactic therapy is indicated after rheumatic fever and acute rheumatic heart disease to prevent further damage to the cardiac valves.

Primary prophylaxis (initial course of antibiotics administered to eradicate the streptococcal infection) also serves as the first course of secondary prophylaxis (prevention of recurrent rheumatic fever and rheumatic heart disease).

Primary prevention of rheumatic fever consists of prompt diagnosis and treatment of GABHS pharyngitis.

Secondary prevention of acute rheumatic fever is very important, as patients who have had acute rheumatic fever are at high risk for recurrence. [86Furthermore, rheumatic heart disease becomes more severe with each recurrent episode. Some studies have shown that recurrence of acute rheumatic fever can result from nonsymptomatic episodes of GAS pharyngitis. [47 Given this, any patients with a history of acute rheumatic fever and evidence of rheumatic heart disease should receive continuous antibiotic prophylaxis.

The preferred medication for secondary prophylaxis of acute rheumatic fever is an injection of 0.6-1.2 million units (dosing based upon weight) of IM benzathine penicillin G every 4 weeks. Administer the same dosage every 3 weeks in areas where rheumatic fever is endemic, in patients with residual carditis, and in high-risk patients. Although PO penicillin prophylaxis is also effective, data from the World Health Organization indicate that the recurrence risk of GABHS pharyngitis is lower when penicillin is administered parentally. [2Other studies evaluting parenteral versus PO antibiotics as secondary prophylaxis have demonstrated similar results. [48 Some oral alternatives include penicillin V (preferred PO agent, dosed at 250 mg BID), macrolides,and sulfadiazine. If a penicillin allergy has been confirmed in a patient, azithromycin 250 mg or 5 mg/kg once daily is usually the preferred agent used.

The duration of antibiotic prophylaxis is controversial. Continue antibiotic prophylaxis indefinitely for patients at high risk (eg, healthcare workers, teachers, daycare workers) for recurrent GABHS infection. Ideally, one could argue for continuing prophylaxis indefinitely, because recurrent GABHS infection and rheumatic fever can occur at any age; however, the American Heart Association recommends that patients with rheumatic fever without carditis receive prophylactic antibiotics for 5 years or until aged 21 years, whichever is longer. [42Patients with rheumatic fever and carditis but no valve disease should receive prophylactic antibiotics for 10 years or well into adulthood, whichever is longer. Finally, patients with rheumatic fever with carditis and valve disease should receive antibiotics for at least 10 years or until age 40 years.

A study that investigated the difference in clinical manifestations and outcomes between first episode and recurrent rheumatic fever concluded that subclinical carditis occurred only in patients experiencing the first episode, and that all deaths occurred in patients with recurrent rheumatic fever, emphasizing the need for secondary prophylaxis. [49 However, an interesting study by Hand et al demonstrated few patients achieved serum concentrations above 0.02 mg/L of benzylpenicillin G for the majority of the time between injections given as secondary prophylaxis. [50This suggests there is a gap in our current understanding of the true effect of benzylpenicillin G and its associated clinical outcomes seen in rheumatic heart disease.

As noted earlier, although patients with rheumatic heart disease and valve damage previously required empiric antibiotics prior to surgical and dental procedures to help prevent bacterial endocarditis, this is no longer the recommendation. [4243Based upon updated guidelines from the American Heart Association, only a limited number of cardiac conditions now require antibiotic prophlyaxis prior to dental procedures. [4243Patients with rheumatic heart disease and valve damage do not require prophylaxis at this time.

Consultations

In addition to cardiology consultation, complications may require cardiothoracic surgery consultation (heart failure and progressive valve insufficiency) and neurology consultation (chorea, PANDAS [pediatric autoimmune neuropsychiatric disorders associated with streptococcal throat infections]).

Surgical Care

When heart failure persists or worsens after aggressive medical therapy for acute rheumatic heart disease, surgery to decrease valve insufficiency may be life-saving.

About 40% of patients with acute rheumatic heart disease subsequently develop mitral stenosis as adults. In patients with critical stenosis, mitral valvulotomy, percutaneous balloon valvuloplasty, or mitral valve replacement may be indicated. The rheumatic heart valve surgery score (RheSCORE) model has been demonstrated to outperform other scoring systems in predicting hospital mortality in patients referred for surgical management of rheumatic heart disease. [51]

Percutaneous balloon mitral valvuloplasty using the Inoue balloon, initially described in 1984, [52appears to produce good results and has been extensively used in countries with a high incidence of rheumatic fever. The more recently described percutaneously implantable mitral clip may be useful in selected cases of mitral insufficiency; further studies are needed to confirm the utility in rheumatic mitral insufficiency. [53545556 

In the past, due to high rates of recurrent symptoms after annuloplasty or other repair procedures, valve replacement appeared to be the preferred surgical option for patients with high rates of recurrent symptoms after annuloplasty or other repair procedures. However, modifications of standard repair techniques, adherence to the importance of good leaflet coaptation, and strict quality control with stringent use of intraoperative transesophageal echocardiography have all contributed to improved long-term results. [57]

Diet and Activity

The diet should be nutritious and without restrictions except in the patient with congestive heart failure. In these patients, fluid and sodium intake should be restricted. Potassium supplementation may be necessary if steroids or diuretics are used.

Initially, patients should be placed on bed rest, followed by a period of indoor activity before being permitted to return to school. Full activity should not be allowed until the levels of acute phase reactants have returned to normal. Patients with chorea may require a wheelchair and should be on homebound instruction until the abnormal movements resolve.

Long-Term Monitoring

Patients with rheumatic fever usually show significant improvement after the initiation of anti-inflammatory therapy. However, they should not be allowed to resume full activities until all clinical symptoms have abated and laboratory values have returned to normal levels.

Emphasize the importance of prophylaxis against recurrent streptococcal pharyngitis and rheumatic fever with each patient. Each recurrent episode of rheumatic carditis produces further valve damage and increases the likelihood that valve replacement will be required. Patients should remain on antibiotic prophylaxis at least until their early twenties. Many physicians believe that lifelong prophylaxis is appropriate.

Patients should be examined regularly to detect signs of mitral stenosis, pulmonary hypertension, arrhythmias, and congestive heart failure.

MEDICATION


Medication Summary

The discussion of treatment and prevention of group A streptococci (GAS) pharyngitis outlined here are based on the recommendations of the 2010American Heart Association practice guidelines on prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis. [58]

Medical therapy is directed at eliminating the group A streptococcal pharyngitis (if still present), suppressing inflammation from the autoimmune response, and providing supportive treatment for congestive heart failure. Attempts are ongoing to produce vaccines against GAS infection, but these have been limited due to the numerous strains of Streptococcus pyogenes as well as difficulty with cross-reactivity of bacterial proteins with host tissue. [59]

Antibiotics

Class Summary

Antibiotics are used for the initial treatment of group A streptococcal pharyngitis to prevent the first attack of rheumatic fever (primary prophylaxis), for recurrent streptococcal pharyngitis, and for continuous therapy to prevent recurrent rheumatic fever and rheumatic heart disease (secondary prophylaxis).

Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K)

For primary prophylaxis (to decrease likelihood of rheumatic fever by treating GABHS pharyngitis) as well as secondary prophylaxis (to prevent recurrent rheumatic fever/carditis) prophylaxis of rheumatic fever. Although amoxicillin may be used instead, there is no microbiologic advantage. 

Do not use tetracyclines to treat GABHS pharyngitis. For recurrent GABHS pharyngitis, a 10-day course of the same antibiotic may be repeated. Alternate drugs for penicillin-allergic patients include azithromycin, clarithromycin, or clindamycin.

Penicillin G benzathine/penicillin G procaine (Bicillin L-A, Wycillin)

For primary prophylaxis (to decrease likelihood of rheumatic fever by treating GABHS pharyngitis) as well as secondary prophylaxis (to prevent recurrent rheumatic fever/carditis) of rheumatic fever. Used when PO administration of penicillin is not feasible or dependable. IM therapy with penicillin is painful, but the discomfort may be minimized if penicillin G is brought to room temperature before the injection or a combination of benzathine penicillin G and procain penicillin G is used.

The initial course of antibiotics administered to eradicate streptococcal infection also serves as the first course of prophylaxis. An injection of IM benzathine penicillin G every 4 weeks is recommended as a regimen for secondary prevention for most patients in the United States. Administer the same dosage every 3 weeks in areas where rheumatic fever is endemic, in patients with residual carditis, and in high-risk patients.

Amoxicillin (Amoxil, Moxatag (DSC), Trimox)

Amoxicillin may be used instead of penicillin VK for primary prevention of rheumatic fever.

Clarithromycin

Alternate antibiotic for primary prevention of acute rheumatic fever in patients allergic to penicillin.

Azithromycin (Zithromax, Zmax)

Alternate antibiotic for primary prevention of acute rheumatic fever in patients allergic to penicillin.

Clindamycin (Cleocin, Cleocin Pediatric, ClindaMax Vaginal)

Alternate antibiotic for primary prevention of acute rheumatic fever in patients allergic to penicillin.

Sulfadiazine

Sulfadiazine may be used for secondary prevention of rheumatic fever.

Anti-inflammatory Agents

Class Summary

The manifestations of acute rheumatic fever (including carditis) typically respond rapidly to therapy with anti-inflammatory agents. Aspirin, in anti-inflammatory doses, is the drug of choice. Prednisone is added when evidence of worsening carditis and heart failure is noted.

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Aspirin, also called acetylsalicylic acid, inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2. Begin administration immediately after the diagnosis of rheumatic fever is made. Initiation of therapy may mask manifestations of disease.

Prednisone (Deltasone, Orasone)

Predinisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. If moderate to severe carditis is indicated by cardiomegaly, congestive heart failure, or third-degree heart block, 2 mg/kg/d PO should be used in addition to, or in lieu of, salicylate therapy. Prednisone should be continued for 2-4 weeks, depending on the severity of the carditis, and tapered during the last week of therapy. Adverse effects can be minimized by discontinuing prednisone therapy after 2 weeks and adding or maintaining salicylates for an additional 2-4 weeks.

Naproxen (Aleve, Anaprox, Anaprox DS)

Naproxen is an NSAID which is dosed at 10-20 mg/kg/day (maximum: 100 mg/day) in divided doses every 12 hours in children older than 2 years or at 250-500 mg twice daily (maximum: 1250 mg/day) in adults. Naproxen can cause gastrointestinal problems, and this side effect should be monitored.

Therapy for Congestive Heart Failure

Class Summary

Heart failure in rheumatic heart disease is related in part to severe insufficiency of the mitral and aortic valves, and in part to pancarditis. Therapy traditionally has consisted of an inotropic agent (digitalis) in combination with diuretics (furosemide, spironolactone) and afterload reduction (captopril, enalapril).

Digoxin (Lanoxin)

Digoxin is an inotropic agent that was widely used in the past. Currently, its efficacy in congestive heart failure is under review. The potential for toxicity is present. Therapeutic levels and clinical effects are observed more quickly if loading doses of digitalis are administered before routine maintenance doses. Digoxin acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure. Therapeutic digoxin levels are present at trough levels of 1.5-2 ng/mL.

Furosemide (Lasix)

Diuretics are frequently used in conjunction with inotropic agents for patients with congestive heart failure. When used aggressively, furosemide may result in hypokalemia and hypovolemia. There is a risk of hearing loss in premature infants. Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule.

Spironolactone (Aldactone, CaroSpir)

Spironolactone is used in conjunction with furosemide as a potassium-sparing diuretic. It competes with aldosterone for receptor sites in the distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Captopril (Capoten)

Captopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. It is rapidly absorbed, but the bioavailability is significantly reduced with food intake. Captopril achieves a peak concentration in 1 hour and has a short half-life. The drug is cleared by the kidneys. Impaired renal function requires dosage reduction. It is absorbed well PO. Administer at least 1 hour before meals. If added to water, use within 15 minutes.

Captopril can be started at a low dose and titrated upward as needed and as the patient tolerates.

Systemic afterload reduction may be helpful in improving cardiac output, particularly in the setting of mitral and aortic valve insufficiency. Some patients have an unusually large hypotensive response. Use a small starting dose, particularly in patients with hypovolemia.

Enalapril (Vasotec)

Enalapril is indicated for chronic aortic and/or mitral regurgitation. It prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased plasma renin levels and a reduction in aldosterone secretion. Enalapril helps control blood pressure and proteinuria. It decreases the pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance.

Enalapril has a favorable clinical effect when administered over a long period. It helps prevent potassium loss in the distal tubules. The body conserves potassium; thus, less oral potassium supplementation is needed. The goal is to decrease afterload to the left ventricle (by reducing systemic blood pressure and by peripheral vasodilatation).