Pediatric Rheumatic Fever 

Updated: Jun 28, 2016
Author: Thomas K Chin, MD; Chief Editor: Lawrence K Jung, MD 

Overview

Background

Rheumatic fever (RF) is a systemic illness that may occur following group A beta hemolytic streptococcal (GABHS) pharyngitis in children. Rheumatic fever and its most serious complication, rheumatic heart disease (RHD), are believed to result from an autoimmune response; however, the exact pathogenesis remains unclear. Studies in the 1950s during an epidemic on a military base demonstrated 3% incidence of rheumatic fever in adults with streptococcal pharyngitis not treated with antibiotics.[1] Studies in children during the same period demonstrated an incidence of only 0.3%. The incidence of rheumatic fever after GABHS infection is thought to be decreased to less than 1%. Cardiac involvement is reported to occur in 30-70% of patients with their first attack of rheumatic fever and in 73-90% of patients when all attacks are counted.

Clinical manifestations and time course of acute rheumatic fever are shown in the image below.

Clinical manifestations and time course of acute r Clinical manifestations and time course of acute rheumatic fever.

Pathophysiology

Rheumatic fever develops in children and adolescents following pharyngitis with GABHS (ie, Streptococcus pyogenes). The organisms attach to the epithelial cells of the upper respiratory tract and produce a battery of enzymes, which allows 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 elevated leukocyte count. In a small percent of patients, infection leads to rheumatic fever several weeks after the sore throat has resolved. Only infections of the pharynx have been shown to initiate or reactivate rheumatic fever. However, epidemiological associations in certain populations have led to speculation that group A Streptococcus impetigo could predispose to or cause rheumatic fever as well.[1]

Direct contact with oral (PO) or respiratory secretions transmits the organism, and crowding enhances transmission. Patients remain infected for weeks after symptomatic resolution of pharyngitis and may serve as a reservoir for infecting others. Penicillin treatment shortens the clinical course of streptococcal pharyngitis and more importantly prevents the major sequelae.

GABHS organisms are gram-positive cocci, which frequently colonize the skin and oropharynx. These organisms may cause suppurative diseases (eg, pharyngitis, impetigo, cellulitis, myositis, pneumonia, puerperal sepsis). GABHS organisms also may be associated with nonsuppurative diseases (eg, rheumatic fever, acute poststreptococcal glomerulonephritis). Group A streptococci (GAS) elaborate the cytolytic toxins, streptolysins S and O. Of these 2 toxins, streptolysin O induces persistently high antibody titers that provide a useful marker of GAS infection and its nonsuppurative complications. Recent studies using enzyme-linked immunosorbent assays showed a correlation between  anti-streptolysin O and anti-human cardiac myosin antibodies.[2]

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. Surface proteins on the cell wall of the organism may subserotype GAS. The presence of the M protein is the most important virulence factor for GAS infection in humans. More than 120 M protein serotypes or M protein genotypes have been identified,[3] some of which have a long terminal antigenic domain (ie, epitopes) similar to antigens in various components of the human heart.

Rheumatogenic strains are often encapsulated mucoid strains, rich in M proteins, and resistant to phagocytosis. These strains are strongly immunogenic, and anti-M antibodies against the streptococcal infection may cross-react with components of heart tissue (ie, sarcolemmal membranes, valve glycoproteins). Currently, emm typing is felt to be more discriminating than M typing.[3]

Acute RHD often produces a pancarditis, characterized by endocarditis, myocarditis, and pericarditis. Endocarditis is manifested as mitral and aortic valve insufficiency. Severe scarring of the valves develops during a period of months to years after an episode of acute rheumatic fever, and recurrent episodes may cause progressive damage to the valves. The mitral valve is affected most commonly and severely (65-70% of patients); the aortic valve is affected second most commonly (25%).

The tricuspid valve is deformed in only 10% of patients, almost always in association with mitral and aortic lesions, and the pulmonary valve is rarely affected. Severe valve insufficiency during the acute phase may result in congestive heart failure (CHF) and even death (1% of patients). Whether myocardial dysfunction during acute rheumatic fever is primarily related to myocarditis or is secondary to CHF from severe valve insufficiency is not known. When pericarditis is present, it rarely affects cardiac function or results in constrictive pericarditis.

Chronic manifestations occur in adults with previous RHD from residual and progressive valve deformity. RHD is responsible for 99% of mitral valve stenosis in adults, and it may be associated with atrial fibrillation from chronic mitral valve disease and atrial enlargement

Epidemiology

Frequency

United States

Rheumatic fever is now uncommon among children in the United States. The incidence of rheumatic fever and RHD was thought to be decreased in the United States and other industrialized countries during the past 80 years. The prevalence of RHD in the United States was less than 0.05 per 1000 population, with only rare regional outbreaks reported in Tennessee in the 1960s and in Utah[4] , Ohio, and Pennsylvania in the 1980's. While In the early 1900s, incidence was reportedly 5-10 cases per 1000 population. Decreased incidence of rheumatic fever was attributed to the introduction of penicillin or a change in the virulence of the streptococci, while the incidence in other developed countries, such as Italy, was comparable.[5]  However a recent assessment of temporal trends of patients diagnosed with acute rheumatic fever in the United States from 2001-2011 showed that since 2001, national acute rheumatic fever admissions has steadily increased, with a peak in 2005, and decreased thereafter.[6]

International

In contrast to trends in the United States, rheumatic fever and RHD have not decreased in developing countries. Retrospective studies in developing countries demonstrate the highest figures for cardiac involvement and the highest recurrence rates of rheumatic fever.[7] Worldwide, there are over 15 million cases of RHD, with 282,000 new cases and 33,000 deaths from this disease each year.[8]

Mortality/Morbidity

RHD is the major cause of morbidity from rheumatic fever and is the major cause of mitral insufficiency and stenosis in the United States and the world. Variables that correlate with severity of valve disease include the number of previous attacks of rheumatic fever, the length of time between the onset of disease and start of therapy, and sex (the prognosis for females is worse than for males). Insufficiency from acute rheumatic valve disease resolves in 70-80% of patients if they adhere to antibiotic prophylaxis.

Race

Native Hawaiians and Maori (both of Polynesian descent) have a higher incidence of rheumatic fever. Incidence of rheumatic fever in these patients is 13.4 per 100,000 hospitalized children per year, even with antibiotic prophylaxis of streptococcal pharyngitis.[8]

The prevalence is greatest in the South (34.32%) compared to the Northeast (25.05%), Midwest (22.95%), and West (17.69%). Blacks have the highest mortality rate (5.00%) compared to whites (3.01%), Hispanics (1.66%) and Asians (0.89%). As median income decreases, the frequency increases, with patients earning less than $25,000 per year making up 23.74% of admissions.[6]

Sex

Rheumatic fever occurs in equal numbers in males and females. Females with rheumatic fever fare worse than males and have a slightly higher incidence of chorea.

Age

Rheumatic fever is principally a disease of childhood, with a median age of 10 years; However, GABHS pharyngitis is uncommon in children younger than 3 years, and acute rheumatic fever is extremely rare in these younger children in industrialized countries. Although less commonly seen in adults compared with children, rheumatic fever in adults accounts for 20% of cases.

 

Presentation

History

Acute rheumatic fever (RF) is a systemic disease. Thus, patients may present with a large variety of symptoms and complaints.

  • History of an antecedent sore throat 1-5 weeks prior to onset is present in 70% of older children and young adults. Only 20% of younger children can recall an antecedent sore throat.

  • Other symptoms on presentation may include fever, rash, headache, weight loss, epistaxis, fatigue, malaise, diaphoresis, and pallor.

  • Patients also may have chest pain with orthopnea or abdominal pain and vomiting.

  • Finally, history may reveal symptoms more specific to rheumatic fever.

    • Migratory joint pain

    • Nodules under the skin

    • Increased irritability and shortened attention span with personality changes, such as pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS)

    • Motor dysfunction

    • History of previous rheumatic fever

  • Patients with previous rheumatic fever are at a high risk of recurrence.

    • Highest risk of recurrence within 5 years of the initial episode

    • Greater risk of recurrence with younger age at the time of the initial episode

    • Generally, recurrent attacks similar to the initial attack (however, risk of carditis and severity of valve damage increase with each attack)

Physical

Revised in 1992 and again in 2016, the modified Jones criteria provide guidelines for making the diagnosis of rheumatic fever.[9, 10] The Jones criteria differentiate between low risk populations (incidence of acute rheumatic fever in ≤2 per 100,000 school-aged children or all-age rheumatic heart disease prevalence of ≤1 per 1000 population per year), vs. moderate and high risk populations (where the groups may experience an incidence of 153 to 380 cases per 100,000 patients per year in the 5-14 year old age group).[11] .  The new criteria also include a role for echocardiography in addition to a clinical assessment of the heart for a diagnosis of carditis.  The new guidelines are in closer alignment with other international guidelines such as those from the World Health Organization.

The modified Jones criteria for initial acute rheumatic fever require the presence of 2 major, or 1 major and 2 minor criteria for the diagnosis of rheumatic fever.

The modified Jones criteria for recurrent rheumatic fever require the presence of 2 major, or 1 major and 2 minor, or 3 minor criteria for the diagnosis of rheumatic fever.

Having evidence of previous group A streptococci pharyngitis is also necessary.  An exception to the requirement for evidence of previous group A streptococci pharyngitis can be made in patients with chorea and clinical or subclinical (echo diagnosis) evidence of carditis. When minor manifestations alone are present, the exclusion of other more likely causes of the clinical presentation is recommended before a diagnosis of an acute rheumatic fever recurrence is made.

  • Major diagnostic criteria

    • Carditis-clinical and/or subclinical (echo)

    • Polyarthritis (monoarthritis or polyarthralgia are adequate to achieve a major diagnostic criteria in Moderate/High-risk populations; for polyarthralgia exclusion of other more likely causes is also required)

    • Chorea

    • Subcutaneous nodules

    • Erythema marginatum

  • Minor diagnostic criteria

    • Fever ≥38.5o C (≥38o 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 ≥60 mm/h and/or C-reactive protein ≥3.0 mg/dl

  • Notable exceptions to strict adherence to the Jones criteria

    • Chorea: It may occur late and be the only manifestation of rheumatic fever, thus it may be impossible to document previous group A streptococci pharyngitis.

    • Indolent carditis: Patients presenting 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, especially rheumatic heart disease who have supporting evidence of a recent GAS infection and who manifest either a single major or several minor criteria: Distinguishing recurrent carditis from preexisting significant RHD may be impossible.

  • Evidence of previous GAS pharyngitis (One of the following must be present):

    • Positive throat culture or rapid streptococcal antigen test

    • Elevated or rising streptococcal antibody titer (anti-streptolysin O titer or anti-DNASEB)

  • Major clinical manifestations

    • Arthritis

      • 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 (ie, knees, ankles) and migrates to other large joints in the lower or upper extremities (ie, elbows, wrists).

      • Affected joints are painful, swollen, warm, erythematous, and limited in their range of motion. The pain is out of proportion to clinical findings.

      • The arthritis reaches maximum severity in 12-24 hours and persists for 2-6 days (rarely more than 4 wk, but has been reported to persist 44 d) at each site and is migratory but not additive.

      • The arthritis responds rapidly to aspirin, which decreases symptoms in affected joints and prevents further migration of the arthritis.

      • Polyarthritis is more common and more severe in teenagers and young adults than in younger children.

      • Patients suffering multiple attacks may exhibit destructive arthritis (Jaccoud arthritis).

    • Carditis

      • Pancarditis is the most serious complication and the second most common complication of rheumatic fever (50%).

      • In advanced cases, patients may experience of dyspnea, mild-to-moderate chest discomfort, pleuritic chest pain, edema, cough, or orthopnea.

      • Upon physical examination, carditis is most commonly revealed by a new murmur and tachycardia that is out of proportion to the fever. New or changing murmurs traditionally have been considered necessary for a diagnosis of rheumatic valvulitis. The murmurs of acute rheumatic fever are from valve regurgitation, and the murmurs of chronic rheumatic fever are from valve stenosis.

      • Congestive heart failure (CHF) may develop secondary to severe valve insufficiency or myocarditis. Physical findings associated with heart failure include tachypnea, orthopnea, jugular venous distention, rales, hepatomegaly, a gallop rhythm, and peripheral swelling and edema. A pericardial friction rub indicates that pericarditis is present. Increased cardiac dullness to percussion, muffled heart sounds, and a paradoxical pulse are consistent with pericardial effusion and impending pericardial tamponade. Confirm this clinical emergency with ECG, and evacuate the effusion by pericardiocentesis if it is producing hemodynamic compromise.

      • In the newest version of the revised Jones Criteria morphologic and Doppler findings on echocardiogram may supersede auscultatory findings for carditis. Acute morphologic changes in the mitral valve may include annular dilation, chordal elongation, chordal rupture resulting in flail leaflet with severe mitral regurgitation, or prolapse or beading/nodularity of the leaflet tips. Doppler findings should demonstrate regurgitation in at least 2 views, with a pansystolic jet in at least 1. Chronic changes in the mitral valve should 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 2 views, with a pansystolic jet in at least 1.

    • Chorea: In the absence of a family history of Huntington chorea or findings consistent with systemic lupus erythematosus, the diagnosis of acute rheumatic fever is almost certain. A long latency period exists between streptococcal pharyngitis (1-6 mo) and the onset of chorea, and a history of an antecedent sore throat frequently is not obtained. Patients with chorea often do not demonstrate other Jones criteria. Chorea is slightly more common in females than males. Chorea is also known as rheumatic chorea, Sydenham chorea, chorea minor, and St Vitus dance.

    • Poststreptococcal movement disorders

      • Described poststreptococcal movement disorders have included pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) and Tourette syndrome.

      • 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, incidents have been reported in which symptoms wax and wane for several years.

      • The PANDAS disorder appears to have a relapsing-remitting symptom complex characterized by obsessive-compulsive personality disorder. Patients with Sydenham chorea and obsessive-compulsive symptoms tend to show aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions. Neurologic abnormalities include cognitive defects and motoric hyperactivity. The symptoms may also include emotional lability, separation anxiety, and oppositional behaviors, and they are prepubertal in onset.

      • Some have proposed that the streptococcal infection triggers 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 and causes the symptom complex.

    • Erythema marginatum: This characteristic rash, also known as erythema annulare, occurs in 5-13% of patients with acute rheumatic fever. Erythema marginatum begins as 1-cm to 3-cm 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 observed easily, 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 (shown in the image below) has also been reported in association with sepsis, drug reactions, and glomerulonephritis.

      Erythema marginatum, the characteristic rash of ac Erythema marginatum, the characteristic rash of acute rheumatic fever.
    • Subcutaneous nodules: Subcutaneous nodules are now an infrequent manifestation of rheumatic fever. The frequency has declined during 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, scalp, and spinous processes of the lumbar and thoracic vertebrae (attached to the tendon sheath). The nodules are firm, nontender, and free from attachments to the overlying skin, and they range from a few millimeters to 1-2 cm. The nodules number from 1 to dozens, with a mean of 3-4. Histologically, the nodules contain areas resembling the Aschoff bodies observed in the heart. Subcutaneous nodules generally occur several weeks into the disease and resolve within a month. They are strongly associated with severe rheumatic carditis, and in the absence of carditis, question the diagnosis of subcutaneous nodules.

  • Other clinical manifestations

    • Abdominal pain: Abdominal pain usually occurs at the onset of acute rheumatic fever, resembles other conditions with acute microvascular mesenteric inflammation, and may mimic acute appendicitis.

    • Arthralgias: Patients may report arthralgias upon presentation. In the history, determining if the patient has taken aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) is important because these may suppress the full manifestations of the disease. Arthralgia cannot be considered a minor manifestation if arthritis is present.

    • Epistaxis: Epistaxis may be associated with severe protracted rheumatic carditis.

    • Fever: Fevers greater than 39°C with no characteristic pattern are present initially in almost every patient with acute rheumatic fever. The fever may be low grade (38-38.5°C) in children with mild carditis or absent in patients with pure chorea. The fever decreases without antipyretic therapy in approximately 1 week, but low-grade fevers persist for 2-3 weeks.

    • Rheumatic pneumonia: Patients present with the same signs as an infectious pneumonia. Differentiate rheumatic pneumonia from respiratory distress related to CHF.

Causes

Rheumatic fever is believed to result from an autoimmune response; however, the exact pathogenesis remains unclear.

  • Rheumatic fever only develops in children and adolescents following group A beta hemolytic streptococcal (GABHS) pharyngitis, and only infections of the pharynx initiate or reactivate rheumatic fever.

  • 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 felt to involve both the B and T cells of peripheral blood, with infiltration of the heart by T cells. Some believe that an increased production of inflammatory cytokines is the final mechanism of the autoimmune reaction that causes damage to cardiac tissue in RHD. 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.

  • Decreased levels of regulatory T-cells have also been associated with rheumatic heart disease and with increased severity.[12]

  • In utero precursors predisposing to rheumatic heart disease have also been proposed; Eriksson et al suggest increased spiraling of the umbilical cord may increase the risk of developing rheumatic heart disease secondary to presumed changes in hemodynamic conditions during formation of the mitral valve.[13]

 

DDx

Diagnostic Considerations

The differential diagnosis for the individual manifestations of pediatric rheumatic fever (arthritis, carditis, chorea) are listed below:

Differential Diagnoses

 

Workup

Laboratory Studies

The following studies are indicated in patients with rheumatic fever (RF):

  • Throat culture

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

    • Throat cultures for GABHS infections usually are negative by the time symptoms of rheumatic fever or rheumatic heart disease (RHD) appear.

    • Make attempts to isolate the organism prior to 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

    • This test allows rapid detection of group A streptococci (GAS) antigen, allowing the diagnosis of streptococcal pharyngitis to be made and antibiotic therapy to be initiated while the patient is still in the physician's office.

    • This test reportedly has a specificity of greater than 95% but a sensitivity of only 60-90%. Thus, obtain a throat culture in conjunction with the rapid antigen detection test.

  • Antistreptococcal antibodies

    • Clinical features of rheumatic fever begin when antistreptococcal antibody levels are at their peak. Thus, these tests are useful for confirming previous GAS infection. Antistreptococcal antibodies are particularly useful in patients who present with chorea as the only diagnostic criterion.

    • Sensitivity for recent infections can be improved by testing for several antibodies. Check antibody titers 2 weeks apart to detect a rising titer. The most common extracellular antistreptococcal antibodies tested include antistreptolysin O (ASO) and anti-DNase B, antihyaluronidase, antistreptokinase, antistreptococcal esterase, and anti–nicotinamide adenine dinucleotide (anti-NAD). Antibody tests for cellular components of GAS antigens include antistreptococcal polysaccharide, antiteichoic acid antibody, and anti-M protein antibody.

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

    • The anti-DNase B has a slightly higher sensitivity (90%) for revealing rheumatic fever or acute glomerulonephritis. Antihyaluronidase frequently is abnormal in patients with rheumatic fever with a normal ASO titer, may rise earlier, and persists longer than elevated ASO titers during incidents of rheumatic fever.

  • Acute-phase reactants: C-reactive protein and erythrocyte sedimentation rate are elevated in individuals with rheumatic fever due to the inflammatory nature of the disease. Both tests have high sensitivity but low specificity for rheumatic fever.

  • Heart reactive antibodies: Tropomyosin is elevated in persons with 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 and may be useful for identifying patients who are at risk of developing rheumatic fever.

Imaging Studies

See the list below:

  • Chest radiography

    • Cardiomegaly, pulmonary congestion, and other findings consistent with heart failure may be observed on chest radiograph in individuals with rheumatic fever (as is shown on the image below).

      Chest radiograph showing cardiomegaly due to cardi Chest radiograph showing cardiomegaly due to carditis of acute rheumatic fever.
    • When the patient has fever and respiratory distress, the chest radiograph helps differentiate between congestive heart failure (CHF) and rheumatic pneumonia.

  • Echocardiography

    • In individuals with acute RHD, echocardiography identified and quantitated valve insufficiency and ventricular dysfunction. Studies in Cambodia and Mozambique demonstrated a 10-fold increase in the prevalence of RHD when echocardiography is used for clinical screening compared with strictly clinical findings.[14]

    • Handheld echocardiography was investigated as a screening tool and found to be 90% sensitive and 92% specific for identifying patients with rheumatic heart disease in Ugandan children.[15]

    • A study by Godown et al. assessed the value of handheld echocardiography over auscultation to identify rheumatic heart disease. The study found that auscultation alone was a poor screening test for rheumatic heart disease and that handheld echocardiography significantly improved detection of rheumatic heart disease and was a cost-effective screening strategy for rheumatic heart disease in resource-limited settings.[16]

    • The World Heart Federation has published guidelines for identifying individuals with rheumatic heard disease without a clear history of acute rheumatic fever. Based on 2-dimensional (2D) imaging and pulsed and color Doppler interrogation, patients are divided into 3 categories: definite rheumatic heart disease, borderline rheumatic heart disease, and normal. For pediatric patients (defined as age < 20 y), definite echo features include pathologic mitral regurgitation (MR) and at least 2 morphological features of rheumatic heart disease of the mitral valve, mitral stenosis mean gradient of more than 4 mm Hg, pathological aortic regurgitation and at least 2 morphological features of rheumatic heart disease of the aortic valve, or borderline disease of both the aortic valve and mitral valve.[17]

    • The revised criteria by the American Heart Association for the diagnosis of acute rheumatic fever was based on the findings above, as well as to align with the World Heart Federation guidelines. In the newest version of the revised Jones Criteria morphologic and Doppler findings on echocardiogram may supersede auscultatory findings for carditis. Acute morphologic changes in the mitral valve may include annular dilation, chordal elongation, chordal rupture resulting in flail leaflet with severe mitral regurgitation, or prolapse or beading/nodularity of the leaflet tips.  Chronic changes in the mitral valve should 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 for the mitral and aortic valves mirrored the recommendations of the World Heart Federation.[10]

    • In persons 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.

    • During acute rheumatic fever, the left ventricle frequently is dilated in association with a normal or increased fractional shortening. Thus, some cardiologists believe that valve insufficiency (eg, from endocarditis), rather than myocardial dysfunction (eg, from myocarditis), is the dominant cause of heart failure in individuals with acute rheumatic fever.

    • In individuals with chronic RHD, echocardiography tracks the progression of valve stenosis and may help determine the time for surgical intervention. The leaflets of affected valves become thickened diffusely, with fusion of the commissures and chordae tendineae. Increased echodensity of the mitral valve may signify calcification.

Other Tests

ECG findings include the following:

  • Sinus tachycardia most frequently accompanies acute RHD. Alternatively, some children develop sinus bradycardia from increased vagal tone. No correlation between bradycardia and severity of carditis is observed.

  • First-degree atrioventricular (AV) block (prolongation of PR interval) is observed in some patients with RHD. 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 RHD. Its presence does not correlate with the development of chronic RHD.

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

  • In individuals with acute pericarditis, ST segment elevation may be present, most marked in leads II, III, aVF, and V4 through V6.

  • Finally, patients with RHD may develop atrial flutter, multifocal atrial tachycardia, or atrial fibrillation from chronic mitral valve disease and atrial dilation.

Procedures

See the list below:

  • Cardiac catheterization is not indicated in acute rheumatic fever.

Histologic Findings

See the list below:

  • Pathologic examination of the insufficient valves may reveal verrucous lesions at the line of closure.

  • Aschoff bodies (ie, 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 eventually are 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.

 

Treatment

Medical Care

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

For patients with GABHS pharyngitis, a meta-analysis supported a protective effect against rheumatic fever (RF) when penicillin is used following the diagnosis.[18]

  • Oral (PO) penicillin V remains the drug of choice for treatment of GABHS pharyngitis, but ampicillin and amoxicillin are equally effective.

  • When PO penicillin is not feasible or dependable, a single dose of intramuscular benzathine penicillin G, or benzathine/procaine penicillin combination is therapeutic.

  • For patients who are allergic to penicillin, administer erythromycin or a first-generation cephalosporin. Other options include clarithromycin for 10 days, azithromycin for 5 days, or a narrow-spectrum (first-generation) cephalosporin for 10 days. As many as 15% of penicillin-allergic patients are also allergic to cephalosporins.

  • Do not use tetracyclines and sulfonamides to treat GABHS pharyngitis.

  • For recurrent group A streptococci (GAS) pharyngitis, a second 10-day course of the same antibiotic may be repeated. Alternate drugs include narrow-spectrum cephalosporins, amoxicillin-clavulanate, dicloxacillin, erythromycin, or other macrolides.

  • Control measures for patients with GABHS pharyngitis are as follows:

    • Hospitalized patients: Place hospitalized patients with GABHS pharyngitis of pneumonia on droplet precautions, as well as standard precautions, until 24 hours after 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 and should undergo antibiotic therapy if infected.

    • School and childcare centers: Children with GABHS infection should not attend school or childcare centers for the first 24 hours after initiating antimicrobial therapy.

  • GABHS carriage is difficult to eradicate with conventional penicillin therapy. Thus, PO clindamycin (20 mg/kg/d PO in 3 divided doses for 10 d) is recommended.

  • In general, antimicrobial therapy is not indicated for pharyngeal carriers of GABHS. Exceptions include the following:

    • Outbreaks of rheumatic fever or poststreptococcal glomerulonephritis

    • Family history of rheumatic fever

    • During outbreaks of GAS pharyngitis in a closed community

    • When tonsillectomy is considered for chronic GABHS carriage

    • When multiple episodes of documented GABHS pharyngitis occur within a family despite appropriate therapy

    • Following GAS toxic shock syndrome or necrotizing fasciitis in a household contact

Treatment for patients with rheumatic fever

Therapy is directed towards eliminating the GABHS pharyngitis (if still present), suppressing inflammation from the autoimmune response, and providing supportive treatment of congestive heart failure (CHF).

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

  • Treatment of the acute inflammatory manifestations of acute rheumatic fever consists of salicylates and steroids. Aspirin in anti-inflammatory doses effectively reduces all manifestations of the disease except chorea, and the response typically is dramatic.

    • If rapid improvement is not observed after 24-36 hours of therapy, question the diagnosis of rheumatic fever.

    • Attempt to obtain aspirin blood levels from 20-25 mg/dL, but stable levels may be difficult to achieve during the inflammatory phase because of variable GI absorption of the drug. Maintain aspirin at anti-inflammatory doses until the signs and symptoms of acute rheumatic fever are resolved or residing (6-8 wk) and the acute phase reactants (APRs) have returned to normal.

    • Anti-inflammatory doses of aspirin may be associated with abnormal liver function tests and GI toxicity, and adjusting the aspirin dosage may be necessary.

    • When discontinuing therapy, withdraw aspirin gradually over weeks while monitoring the APRs for evidence of rebound. Chorea most frequently is self-limited but may be alleviated or partially controlled with phenobarbital or diazepam.

  • If moderate to severe carditis is present as indicated by cardiomegaly, third-degree heart block, or CHF, add PO prednisone to salicylate therapy.

    • Continue prednisone for 2-6 weeks depending on the severity of the carditis, and taper prednisone during the last week of therapy.

    • Discontinuing prednisone therapy after 2-4 weeks, while maintaining salicylates for an additional 2-4 weeks, can minimize adverse effects.

  • Include digoxin and diuretics, afterload reduction, supplemental oxygen, bed rest, and sodium and fluid restriction as additional treatment for patients with acute rheumatic fever and CHF. The diuretics most commonly used in conjunction with digoxin for children with CHF include furosemide and spironolactone.

    • Initiate digoxin only after checking electrolytes and correcting abnormalities in serum potassium.

    • The total loading dose is 20-30 mcg/kg PO every day, with 50% of the dose administered initially, followed by 25% of the dose 8 hours and 16 hours after the initial dose. Maintenance doses typically are 8-10 mcg/kg/d PO in 2 divided doses. For older children and adults, the total loading dose is 1.25-1.5 mg PO, and the maintenance dose is 0.25-0.5 mg PO every day. Therapeutic digoxin levels are present at trough levels of 1.5-2 ng/mL.

  • Afterload reduction (ie, using ACE inhibitor captopril) 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 only after correcting hypovolemia.

  • When heart failure persists or worsens during the acute phase after aggressive medical therapy, surgery is indicated to decrease valve insufficiency.

Treatment for patients following rheumatic heart disease (RHD)

Preventive and prophylactic therapy is indicated after rheumatic fever and RHD to prevent further damage to 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 RHD).

  • An injection of 0.6-1.2 million units of benzathine penicillin G intramuscularly every 4 weeks is the recommended regimen for secondary prophylaxis for most US patients. 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.

    • The duration of antibiotic prophylaxis is controversial. Continue antibiotic prophylaxis indefinitely for patients at high risk (eg, health care workers, teachers, daycare workers) for recurrent GABHS infection. Ideally, continue prophylaxis indefinitely, because recurrent GABHS infection and rheumatic fever can occur at any age; however, the American Heart Association currently recommends that patients with rheumatic fever without carditis receive prophylactic antibiotics for 5 years or until aged 21 years, whichever is longer.[19] Patients with rheumatic fever with 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 at least 10 years or until aged 40 years.

    • Patients with RHD and valve damage require a single dose of antibiotics 1 hour before surgical and dental procedures to help prevent bacterial endocarditis. Patients who had rheumatic fever without valve damage do not need endocarditis prophylaxis. Do not use penicillin, ampicillin, or amoxicillin for endocarditis prophylaxis in patients already receiving penicillin for secondary rheumatic fever prophylaxis (relative resistance of PO streptococci to penicillin and aminopenicillins). Alternate drugs recommended by the American Heart Association for these patients include PO clindamycin (20 mg/kg in children, 600 mg in adults) and PO azithromycin or clarithromycin (15 mg/kg in children, 500 mg in adults). Additional guidelines for endocarditis prophylaxis in patients who are allergic to penicillin or who are unable to receive PO antibiotics are discussed in the Bacterial Endocarditis article.

    • A recent study investigated the difference in clinical manifestations and outcomes between first episode and recurrent rheumatic fever.[20] The study 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.

Surgical Care

When heart failure persists or worsens after aggressive medical therapy for acute RHD, surgery to decrease valve insufficiency may be lifesaving. Approximately 40% of patients with acute rheumatic fever subsequently develop mitral stenosis as adults. Mitral valvulotomy, percutaneous balloon valvuloplasty, or mitral valve replacement may be indicated in patients with critical stenosis. Traditionally, valve replacement appears to be the preferred surgical option for patients with high rates of recurrent symptoms after annuloplasty or other repair procedures. However, recent 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 the improved long-term results.[21]

Diet

Advise nutritious diet without restrictions except in patients with CHF, who should follow a fluid-restricted and sodium-restricted diet. Potassium supplementation may be necessary because of the mineralocorticoid effect of corticosteroid and the diuretics, if used.

Activity

Initially, place patients on bed rest, followed by a period of indoor activity before they are permitted to return to school. Do not allow full activity until the APRs have returned to normal. Patients with chorea may require a wheelchair and should be on homebound instruction until the abnormal movements resolve.

 

Medication

Medication Summary

Treatment and prevention of group A streptococci pharyngitis outlined here are based on the current recommendations of the American Heart Association Practice Guidelines on Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis.[22] Medical therapy is directed toward elimination of GAS pharyngitis (if still present), suppression of inflammation from the autoimmune response, and supportive treatment of congestive heart failure (CHF). Attempts are being made to produce vaccines against GAS infection, but the vaccines will not be available for years.

Antibiotics for endocarditis prophylaxis are administered to patients with certain cardiac conditions, such as carditis caused by rheumatic fever, before procedures that may cause bacteremia are performed. For more information, see Antibiotic Prophylactic Regimens for Endocarditis.

Antibiotics

Class Summary

The roles for antibiotics are to (1) initially treat GABHS pharyngitis, (2) prevent recurrent streptococcal pharyngitis, rheumatic fever (RF), and rheumatic heart disease (RHD), and (3) provide prophylaxis against bacterial endocarditis.

Penicillin VK (Beepen-VK, Pen.Vee K, V-Cillin K, Veetids)

For  primary (decrease likelihood of rheumatic fever by treatment of GABHS pharyngitis) as well as secondary (prevention of 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 second 10-d course of the same antibiotic may be repeated. Alternate drugs (penicillin allergic patients) include azithromycin, clarithromycin or clindamycin.

Penicillin G benzathine/penicillin G procaine (Bicillin C-R, Bicillin C-R 900/300)

For primary (decrease likelihood of rheumatic fever by treatment of GABHS pharyngitis) as well as secondary (prevention of recurrent rheumatic fever/carditis) prophylaxis of rheumatic fever. Used when PO administration of penicillin is not feasible or dependable. IM therapy with penicillin is painful, but discomfort may be minimized if penicillin G is brought to room temperature before injection or combination of benzathine penicillin G and procaine penicillin G is used. Initial course of antibiotics administered to eradicate streptococcal infection also serves as first course of prophylaxis. An injection of benzathine penicillin G IM q4wk is recommended regimen for secondary prevention for most United States patients. Administer same dosage q3wk in areas where RF is endemic, in patients with residual carditis, and in high-risk patients.

Amoxicillin (Amoxil, Biomox, Trimox)

May be used instead of Penicillin VK for primary prevention of rheumatic fever

Clarithromycin (Biaxin)

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

Azithromycin (Zithromax)

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

May be used for secondary prevention of rheumatic fever

Anti-inflammatory agents

Class Summary

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

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Begin administration immediately after diagnosis of RF. Initiation of therapy may mask manifestations of disease.

Prednisone (Deltasone, Orasone)

If moderate-to-severe carditis is present as indicated by cardiomegaly, CHF, or third-degree heart block, use 2 mg/kg/d PO prednisone in addition to or in lieu of salicylate therapy. Continue prednisone for 2-4 wk depending on severity of carditis and taper during last week of therapy. Discontinuing prednisone therapy after 2 wk while adding or maintaining salicylates for additional 2-4 wk may minimize adverse effects.

Therapy for congestive heart failure

Class Summary

Heart failure in RHD probably 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).

Digoxin (Lanoxin, Lanoxicaps)

Inotropic agent widely used in past. Its efficacy in CHF is under review. 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. 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.

Captopril (Capoten)

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

Furosemide (Lasix)

Diuretics frequently are used in conjunction with inotropic agents for patients with CHF. When used aggressively, may result in hypokalemia and hypovolemia. Risk of hearing loss in premature infants.

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.

Spironolactone (Aldactone)

Used in conjunction with furosemide as potassium-sparing diuretic.

Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

 

Follow-up

Further Outpatient Care

See the list below:

  • Patients with rheumatic fever (RF) usually demonstrate significant improvement after initiation of anti-inflammatory therapy; however, do not allow patients to resume full activities until all clinical symptoms and laboratory values have returned to normal.

  • Emphasize the importance of prophylaxis against recurrent streptococcal pharyngitis and rheumatic fever. Each recurrent episode of rheumatic carditis produces further valve damage and the likelihood of valve replacement. Patients should remain on antibiotic prophylaxis at least until the early third decade of life. Many physicians believe lifelong prophylaxis is appropriate.

  • Monitor patients routinely for the signs and symptoms of mitral stenosis, pulmonary hypertension, arrhythmia, and congestive heart failure (CHF).

Complications

See the list below:

  • Potential complications include CHF from valve insufficiency (acute rheumatic fever) or stenosis (chronic rheumatic fever).

  • Associated cardiac complications include atrial arrhythmias, pulmonary edema, recurrent pulmonary emboli, infective endocarditis, thrombus formation, and systemic emboli.

Prognosis

See the list below:

  • The manifestations of acute rheumatic fever resolve during a period of 12 weeks in 80% of patients and may extend as long as 15 weeks in the remaining 20% of patients.

  • Rheumatic fever was the leading cause of death in patients aged 5-20 years in the United States 100 years ago. At that time, the mortality rate was 8-30% from carditis and valvulitis but decreased to a 1-year mortality rate of 4% by the 1930s. Following the development of antibiotics, the mortality rate decreased to nearly 0% by the 1960s in the United States. However, the mortality rate has remained 1-10% in developing countries.

  • The development of penicillin also has affected the likelihood of developing chronic valvular disease after an episode of acute rheumatic fever. Prior to penicillin, 60-70% of patients developed valve disease; since the introduction of penicillin, 9-39% of patients develop valve disease.

  • In patients who developed murmurs from valve insufficiency from acute rheumatic fever, numerous factors (eg, severity of initial carditis, presence or absence of recurrences, amount of time since episode of rheumatic fever) affected the likelihood that valve abnormalities and the murmur would disappear. The type of treatment and the promptness of its initiation did not affect the likelihood that the murmur would disappear. In general, incidence of residual rheumatic heart disease (RHD) at 10 years was 34% in patients without recurrences but was 60% in patients with recurrent rheumatic fever. In patients in whom the murmur disappeared, it did so within 5 years in 50%. Thus, a significant number of patients experience resolution of valve abnormalities even 5-10 years after their episode of rheumatic fever.

  • The importance of preventing recurrences of rheumatic fever is evident.

Patient Education

See the list below:

  • Emphasize measures that minimize further damage to the valves of the heart.

  • Timely evaluation and treatment of pharyngitis in children help prevent rheumatic fever.

  • Secondary prophylaxis of patients with previous rheumatic fever and valve involvement with penicillin injections every 3-4 weeks decrease the recurrence of RHD.

  • Additional prophylactic antibiotics prior to dental and surgical procedures decrease the likelihood of bacterial endocarditis.