AUTHOR INFORMATION

Section 1 of 10

Authored by Thomas K Chin, MD, Associate Professor in Pediatrics, University of Tennessee College of Medicine; Chief, Department of Pediatric Cardiology, LeBonheur Children's Hospital, St Jude Children's Research Hospital

Coauthored by Clyde Worley, MD, Staff Physician, Departments of Pediatrics and Internal Medicine, Vanderbilt University Medical Center; Douglas Li, BS, Wake Forest University Medical Center

Thomas K Chin, MD, is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, American Society for Pharmacology and Experimental Therapeutics, American Society of Echocardiography, and Society for Pediatric Research

Edited by Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Thomas JA Lehman, MD, Clinical Professor of Pediatrics, Weill-Cornell University; Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Hospital for Special Surgery; Gilbert Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; and Barry L Myones, MD, Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital at Houston; Associate Professor, Departments of Pediatrics & Immunology, Pediatric Rheumatology Section, Baylor College of Medicine

Author's Email:	Thomas K Chin, MD
Editor's Email:	Barry L Myones, MD

eMedicine Journal, March 27 2006, VOLUME 7, Number 3

INTRODUCTION

Section 2 of 10

Background: Rheumatic fever (RF) is a systemic illness that may occur following group A beta hemolytic streptococcal (GABHS) pharyngitis in children. RF 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 RF in adults with streptococcal pharyngitis not treated with antibiotics. Studies in children during the same period demonstrated an incidence of only 0.3%. Cardiac involvement is reported to occur in 30-70% of patients with their first attack of RF and in 73-90% of patients when all attacks are counted.

Pathophysiology: RF 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 RF several weeks after the sore throat has resolved. Only infections of the pharynx initiate or reactivate RF.

Direct contact with oral 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, RF, 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.

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 90 M serotypes have been identified, some of which have a long terminal antigenic domain (ie, epitopes) similar to antigens in various components of the human heart. Rheumatogenic strains often are encapsulated mucoid strains, rich in M proteins, and resistant to phagocytosis. These strains are strongly immunogenic, and anti-M antibodies against the streptococcal infection may cross-react with components of heart tissue (ie, sarcolemmal membranes, valve glycoproteins).

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 RF, 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 rarely is 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 RF is related primarily 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.

Frequency:

• In the US: RF is now uncommon among children in the US. Incidence of RF and RHD has decreased in the US and other industrialized countries during the past 80 years. Prevalence of RHD in the US is now less than 0.05 per 1000 population, with rare regional outbreaks reported in Tennessee in the 1960s and in Utah, Ohio, and Pennsylvania in the 1980s. In the early 1900s, incidence was reportedly 5-10 cases per 1000 population. Decreased incidence of RF has been attributed to the introduction of penicillin or a change in the virulence of the streptococci.

• Internationally: In contrast to trends in the US, RF 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 RF. Worldwide, an estimated 5-30 million children and young adults have chronic RHD, and 90,000 patients die from this disease each year.

Mortality/Morbidity: RHD is the major cause of morbidity from RF, and it is the major cause of mitral insufficiency and stenosis in the United States and the world. Variables that correlate with severity of valve disease are the number of previous attacks of RF, 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 RF. Incidence of RF in these patients is 13.4 per 100,000 hospitalized children per year, even with antibiotic prophylaxis of streptococcal pharyngitis. Otherwise, race (when controlled for socioeconomic variables) has not been documented to influence the disease incidence.

Sex: RF occurs in equal numbers in males and females. Females with RF fare worse than males and have a slightly higher incidence of chorea.

Age: RF is principally a disease of childhood, with a median age of 10 years; however, RF also occurs in adults (20% of cases).

CLINICAL

Section 3 of 10

History: Acute 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 RF.


• • 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 RF
  
  
  
• Patients with previous RF 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, the modified Jones criteria provide guidelines for making the diagnosis of RF. The Jones criteria require the presence of 2 major or 1 major and 2 minor criteria for the diagnosis of RF. Having evidence of previous GAS pharyngitis is also necessary. These criteria are not absolute, and the diagnosis of RF can be made in patients with only confirmed streptococcal pharyngitis and chorea.

• Major diagnostic criteria


• • Carditis

  • Polyarthritis

  • Chorea

  • Subcutaneous nodules

  • Erythema marginatum
  
  
  
• Minor diagnostic criteria


• • Fever

  • Arthralgia

  • Prolonged PR interval on electrocardiogram

  • Elevated acute-phase reactants (APRs), which are erythrocyte sedimentation rate and C-reactive protein
  
  
  
• Three notable exceptions to strict adherence to the Jones criteria


• • Chorea: It may occur late and be the only manifestation of RF.
  
  
  
  • Indolent carditis: Patients presenting late to medical attention months after the onset of RF may have insufficient support to fulfill the criteria.
  
  
  
  • Newly ill patients with a history of RF, especially RHD, 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
  
  
  
• Major clinical manifestations


• • Arthritis: Polyarthritis is the most common symptom and frequently is the earliest manifestation of acute RF (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 RF (50%). In advanced cases, patients may experience of dyspnea, mild-to-moderate chest discomfort, pleuritic chest pain, edema, cough, or orthopnea. On 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 RF are from valve regurgitation, and the murmurs of chronic RF are from valve stenosis.

    Frequently examine patients in whom the diagnosis of acute RF is made due to the progressive nature of the disease. Some cardiologists have proposed that evidence of new mitral regurgitation from Doppler echocardiography, even in the absence of accompanying auscultatory findings, may be sufficient for making the diagnosis of carditis, particularly if the echo findings resolve along with other manifestations of RF. This criterion for carditis is not accepted uniformly and remains specifically excluded in the 1992 revised Jones criteria because of insufficient data at the time of publication.

    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.

  
  
  
  • Carditis: Pancarditis is the most serious complication and the second most common complication of RF (50%). In advanced cases, patients may experience of dyspnea, mild-to-moderate chest discomfort, pleuritic chest pain, edema, cough, or orthopnea. On 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 RF are from valve regurgitation, and the murmurs of chronic RF are from valve stenosis.

    In the absence of a family history of Huntington chorea or findings consistent with systemic lupus erythematosus, the diagnosis of acute RF 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 also is known as rheumatic chorea, Sydenham chorea, chorea minor, and St Vitus dance. Described poststreptococcal movement disorders have included pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (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 RF. Erythema marginatum begins as 1- 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 has also been reported in association with sepsis, drug reactions, and glomerulonephritis.

  • Subcutaneous nodules: Subcutaneous nodules are now an infrequent manifestation of RF. The frequency has declined during the past several years to 0-8% of patients with RF. 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 RF, 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 RF. The fever may be low grade (38.0-38.5°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: RF is believed to result from an autoimmune response; however, the exact pathogenesis remains unclear.

• RF only develops in children and adolescents following GABHS pharyngitis, and only infections of the pharynx initiate or reactivate RF.



• 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 RF. 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.

DIFFERENTIALS

Section 4 of 10

Acute Poststreptococcal Glomerulonephritis
Aortic Stenosis, Valvar
Aortic Valve Insufficiency
Aortic Valve, Bicuspid
Arthritis, Septic
Cardiomyopathy, Dilated
Endocarditis, Bacterial
Gonorrhea
Heart Failure, Congestive
Kawasaki Disease
Lyme Disease
Mitral Valve Insufficiency
Mitral Valve Prolapse
Myocarditis, Nonviral
Myocarditis, Viral
Pericardial Effusion, Malignant
Pericarditis, Bacterial
Pericarditis, Viral
Sarcoidosis
Serum Sickness
Sickle Cell Anemia
Splenomegaly
Takayasu Arteritis
Tuberculosis
Wilson Disease

Other Problems to be Considered:

Arthritis and/or arthralgias
Rheumatoid arthritis
Reactive arthritis
Dermatomyositis
Erythema nodosum
Henoch-Schönlein purpura
Lupus erythematosus in infants and children
Poststreptococcal syndrome
Controversy exists as to whether the entity of poststreptococcal reactive arthritis (PSRA) is along the clinical continuum of RF or is a separate clinical entity. PSRA is characterized by objective arthritis in the setting of a vigorous immune response to streptococcal antigens; however, the arthritis is nonmigratory and poorly responsive to aspirin. Children with PSRA do not fulfill modified Jones criteria. Most pediatric rheumatologists treat PSRA with the same antibiotic prophylaxis provided to individuals with RF.

Chorea
Drug reaction (eg, oral contraceptive pills, phenytoin, haloperidol, amitriptyline, metoclopramide, fluphenazine)
Huntington chorea
Chorea gravidum
Periarteritis nodosa

Erythema marginatum
Drug reactions

Subcutaneous nodules
Rheumatoid arthritis

WORKUP

Section 5 of 10

Lab Studies:

• Throat culture


• • Throat cultures for GABHS infections usually are negative by the time symptoms of RF or 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 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 RF 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 RF), the sensitivity of this test is 80-85%.
  
  
  
  • The anti-DNase B has a slightly higher sensitivity (90%) for revealing RF or acute glomerulonephritis. Antihyaluronidase frequently is abnormal in patients with RF with a normal ASO titer, may rise earlier, and persists longer than elevated ASO titers during incidents of RF.
  
  
  
• Acute-phase reactants: C-reactive protein and erythrocyte sedimentation rate are elevated in individuals with RF due to the inflammatory nature of the disease. Both tests have high sensitivity but low specificity for RF.



• Heart reactive antibodies: Tropomyosin is elevated in persons with acute RF.


• • Rapid detection test for D8/17: This immunofluorescence technique for identifying the B-cell marker D8/17 is positive in 90% of patients with RF, and it may be useful for identifying patients who are at risk of developing RF.
  
  
  

Imaging Studies:

• Chest radiography


• • Cardiomegaly, pulmonary congestion, and other findings consistent with heart failure may be observed on chest radiograph in individuals with RF.
  
  
  
  • When the patient has fever and respiratory distress, the chest radiograph helps differentiate between CHF and rheumatic pneumonia.
  
  
  
• Echocardiography


• • In individuals with acute RDH, echocardiography identifies and quantitates valve insufficiency and ventricular dysfunction.
  
  
  
  • 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 RF, 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 RF.
  
  
  
  • 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


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

• Cardiac catheterization: This study is not indicated in acute RF.

TREATMENT

Section 6 of 10

Medical Care: Direct medical therapy toward eliminating the GAS pharyngitis (if still present), suppressing inflammation from the autoimmune response, and providing supportive treatment of CHF. A recent metaanalysis has supported a protective effect against rheumatic fever when penicillin is used following the diagnosis of GAS pharyngitis. Oral penicillin V remains the drug of choice for treatment of GAS pharyngitis. When oral penicillin is not feasible or dependable, a single dose of intramuscular benzathine penicillin G 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 GAS pharyngitis.

• For recurrent 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.

• GAS carriage is difficult to eradicate with conventional penicillin therapy. Thus, oral 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 GAS. Exceptions include the following:
  • Outbreaks of RF or poststreptococcal glomerulonephritis

  • Family history of RF

  • During outbreaks of GAS pharyngitis in a closed community

  • When tonsillectomy is considered for chronic GAS carriage

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

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



• Treatment of the acute inflammatory manifestations of acute RF 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 RF.

  • 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 RF 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, CHF, or third-degree heart block, add oral 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 RF 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 qd, with 50% of the dose administered initially, followed by 25% of the dose 8 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 qd. 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.



• Preventive and prophylactic therapy is indicated after RF 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 RF 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 RF is endemic, in patients with residual carditis, and in high-risk patients.

  • Although oral penicillin prophylaxis is also effective, data from the World Health Organization indicate that the recurrence risk of GAS 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 GAS infection. Ideally, continue prophylaxis indefinitely, because recurrent GAS infection and RF can occur at any age; however, the American Heart Association currently recommends that patients with RF without carditis receive prophylactic antibiotics for 5 years or until aged 21 years, whichever is longer. Patients with RF with carditis but no valve disease should receive prophylactic antibiotics for 10 years or well into adulthood, whichever is longer. Finally, patients with RF 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 RF 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 RF prophylaxis (relative resistance of oral streptococci to penicillin and aminopenicillins). Alternate drugs recommended by the American Heart Association for these patients include oral clindamycin (children: 20 mg/kg; adults: 600 mg) and oral azithromycin or clarithromycin (children: 15 mg/kg; adults: 500 mg). Additional guidelines for endocarditis prophylaxis in patients who are allergic to penicillin or who are unable to receive oral antibiotics are discussed in the Bacterial Endocarditis article.




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

  • Hospitalized patients: Place hospitalized patients with GAS 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 GAS infection and should undergo antibiotic therapy if infected.

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

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 RF subsequently develop mitral stenosis as adults. Mitral valvulotomy, percutaneous balloon valvuloplasty, or mitral valve replacement may be indicated in patients with critical stenosis. Valve replacement appears to be the preferred surgical option for patients with high rates of recurrent symptoms after annuloplasty or other repair procedures.

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

Section 7 of 10

Treatment and prevention of GAS pharyngitis outlined here are based on the current recommendations of the Committee on Infectious Disease (American Academy of Pediatrics). Medical therapy is directed toward elimination of GAS pharyngitis (if still present), suppression of inflammation from the autoimmune response, and supportive treatment of 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.

Drug Category: Antibiotics -- The roles for antibiotics are to (1) initially treat GAS pharyngitis, (2) prevent recurrent streptococcal pharyngitis, RF, and RHD, and (3) provide prophylaxis against bacterial endocarditis.

Drug Name	Penicillin VK (Beepen-VK, Pen.Vee K, V-Cillin K, Veetids) -- DOC for treatment of GAS pharyngitis. Although ampicillin or amoxicillin may be used instead, they have no microbiologic advantage. Do not use tetracyclines and sulfonamides to treat GAS pharyngitis. For recurrent GAS pharyngitis, a second 10-d course of same antibiotic may be repeated. Alternate drugs include narrow-spectrum cephalosporins, amoxicillin-clavulanate, dicloxacillin, erythromycin, or other macrolides.
Adult Dose	500 mg PO bid/tid for 10 d
Pediatric Dose	Children: 250 mg (400,000 U) PO bid/tid for 10 d Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing decrease in effectiveness of penicillins when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Renal impairment, anaphylaxis, thrombocytopenia

Drug Name	Benzathine (Bicillin L-A)/procaine penicillin (Crysticillin A.S., Wycillin) -- 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.
Adult Dose	Eradication: 1.2 million U of benzathine penicillin G or a combination of 900,000 U of benzathine penicillin G with 300,000 U of procaine penicillin G IM as a single dose Secondary prevention: Administer eradication dose q3wk (in high-risk areas, high-risk patients) or q4wk (for most areas in United States)
Pediatric Dose	Eradication <60 lb: 600,000 U of benzathine penicillin G IM as a single dose Secondary prevention: Administer eradication dose q3wk (in high-risk areas, high-risk patients) or q4wk (for most areas in United States)
Contraindications	Documented hypersensitivity
Interactions	Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion, increasing penicillin serum concentrations
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Never use IV route to administer penicillin G procaine; impaired renal function; anaphylaxis; thrombocytopenia

Drug Name	Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin) -- Used for patients who are allergic to penicillin. Other options include clarithromycin, azithromycin, or a narrow-spectrum cephalosporin (ie, cephalexin). As many as 15% of penicillin-allergic patients also are allergic to cephalosporins.
Adult Dose	250 mg erythromycin stearate/base (or 400 mg ethylsuccinate) q6h PO 1 h ac for 10 d
Pediatric Dose	20-40 mg (as base, estolate, or stearate)/kg/d PO divided bid/qid for 10 d; not to exceed 1 g/d Alternatively, 40 mg (as ethylsuccinate)/kg/d PO divided bid/qid for 10 d
Contraindications	Documented hypersensitivity; with terfenadine (off US market) or astemizole (use in combination with erythromycin may cause prolongation of QT interval, with increased risk of ventricular arrhythmias and sudden death)
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occurs

Drug Name	Clarithromycin (Biaxin) -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose	250-500 mg PO bid for 10 d
Pediatric Dose	7.5 mg/kg PO bid for 10 d
Contraindications	Documented hypersensitivity; coadministration of pimozide; patients taking terfenadine (off US market); patients with long QT syndrome
Interactions	CYP450 1A2 and 3A4 inhibitor; toxicity increases with coadministration of fluconazole and pimozide; clarithromycin effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, and HMG CoA-reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; administer one half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Azithromycin (Zithromax) -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose	12 mg/kg (not to exceed 500 mg) PO qd for 5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated

Drug Name	Cephalexin (Keflex, Biocef, Keftab) -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose	250-500 mg PO qid for 10 d
Pediatric Dose	25-50 mg/kg/d PO divided qid for 10 d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with aminoglycosides increases nephrotoxic potential
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Name	Amoxicillin (Amoxil, Biomox, Trimox) -- DOC used for bacterial endocarditis prophylaxis. Administered as single PO dose 1 h before dental work or surgery.
Adult Dose	2 g PO once as a single dose
Pediatric Dose	50 mg/kg PO once as a single dose
Contraindications	Documented hypersensitivity
Interactions	None significant for prophylaxis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Category: Anti-inflammatory agents -- Manifestations of acute RF (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 exists.

Drug Name	Aspirin (Anacin, Ascriptin, Bayer Aspirin) -- Begin administration immediately after diagnosis of RF. Initiation of therapy may mask manifestations of disease.
Adult Dose	4-8 g/d PO divided q4-6h; maintain aspirin levels in 20-25 mg/dL range until all symptoms have resolved and APRs have returned to normal
Pediatric Dose	80-100 mg/kg/d PO divided q4-6h; maintain aspirin levels in 20-25 mg/dL range until all symptoms have resolved and APRs have returned to normal
Contraindications	Documented hypersensitivity; liver damage; hypoprothrombinemia, vitamin K deficiency; bleeding disorders; asthma
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	Risk of salicylate intoxication and poisoning; watch for hyperventilation with prolonged expiratory phase with respiratory alkalosis and metabolic acidosis; risk of tinnitus, GI discomfort, and ulceration; when taken during pregnancy, increased risk of pulmonary hypertension exists in fetus in neonatal period

Drug Name	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.
Adult Dose	2 mg/kg/d PO for 2-4 wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Therapy for congestive heart failure -- 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).

Drug Name	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.
Adult Dose	Total digitalizing dose (TDD) to be administered over 24 h; first dose is one half the TDD; second dose is one fourth the TDD, given 8 h later; third dose is one fourth the TDD, given 8 h after the second TDD: 0.75-1.5 mg PO Maintenance dose: 0.125-0.5 mg PO qd
Pediatric Dose	TDD to be administered over 24 h; first dose is one half the TDD; second dose is one fourth the TDD, given 8 h later; third dose is one fourth the TDD, given 8 h after the second TDD: Preterm infant: 20-30 mcg/kg PO Term infant: 25-35 mcg/kg PO 1 month to 2 years: 35-60 mcg/kg PO 2-5 years: 30-40 mcg/kg PO 5-10 years: 20-35 mcg/kg PO >10 years: Administer as in adults Maintenance dose: Preterm infant: 5-7.5 mcg/kg/d PO divided bid Term infant: 6-10 mcg/kg/d PO divided bid 1 month to 2 years: 10-15 mcg/kg/d PO divided bid 2-5 years: 7.5-10 mcg/kg/d PO divided bid 5-10 years: 5-10 mcg/kg/d PO divided bid >10 years: Administer as in adults
Contraindications	Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
Interactions	Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, PO amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil Medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, PO colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (eg, carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias in patients receiving digitalis; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; caution in hypothyroidism, hypoxia, and acute myocarditis; initiate digoxin only after checking electrolytes and correcting abnormalities in serum potassium

Drug Name	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.
Adult Dose	Starting dose: 6.25-12.5 mg PO tid Typical dose: 50-100 mg PO tid
Pediatric Dose	Starting dose: 0.1-0.5 mg/kg/d PO divided tid; typically 1-2 mg/kg/d PO divided tid
Contraindications	Documented hypersensitivity; renal impairment
Interactions	NSAIDs may reduce hypotensive effects of captopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases captopril levels; probenecid may increase captopril levels; hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in second and third trimesters; caution in renal impairment, valvular stenosis, or severe CHF

Drug Name	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.
Adult Dose	20-40 mg PO/IV/IM bid/tid
Pediatric Dose	1-2 mg/kg/dose PO/IV/IM qd/tid
Contraindications	Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions	Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced with concurrent administration; increased plasma lithium levels and toxicity are possible with concurrent administration
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Obtain frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Drug Name	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.
Adult Dose	100 mg PO divided qd/bid
Pediatric Dose	2-4 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; anuria; renal failure; hyperkalemia
Interactions	May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity of spironolactone
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal and hepatic impairment

FOLLOW-UP

Section 8 of 10

Further Outpatient Care:

• Patients 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 RF. 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 CHF.

Complications:

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



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

Prognosis:

• The manifestations of acute RF 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.



• RF was the leading cause of death in patients aged 5-20 years in the US 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 US. 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 RF. 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 RF, numerous factors (eg, severity of initial carditis, presence or absence of recurrences, amount of time since episode of RF) 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 RHD at 10 years was 34% in patients without recurrences but was 60% in patients with recurrent RF. 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 RF.



• The importance of preventing recurrences of RF is evident.

Patient Education:

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


• • Timely evaluation and treatment of pharyngitis in children help prevent RF.
  
  
  
  • Secondary prophylaxis of patients with previous RF 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.
  
  
  

TEST QUESTIONS

Section 9 of 10

CME Question 1: Acute rheumatic fever (RF) is suggested in a patient. He has evidence of antecedent group A beta-hemolytic streptococcal pharyngitis, based on a positive throat culture. Which of the findings is adequate to make a diagnosis of RF?

A: Arthritis and fever
B: Fever, arthralgia, and a prolonged PR interval on ECG
C: Erythema marginatum and arthralgia
D: Carditis and a positive antistreptolysin O titer
E: New-onset chorea, demonstrated not to be Huntington chorea

The correct answer is E: The diagnosis of RF requires evidence of antecedent group A streptococcal pharyngitis and fulfillment of the Jones criteria (presence of 2 major or 1 major and 2 minor diagnostic manifestations). The single exception for a diagnosis of RF is new-onset chorea, if antecedent streptococcal pharyngitis is present and Huntington chorea has been excluded.

CME Question 2: A 16-year-old boy is diagnosed with acute rheumatic fever (RF) based upon the presence of antecedent group A beta-hemolytic streptococcal pharyngitis infection, erythema marginatum, and subcutaneous nodules. An electrocardiogram demonstrates first-degree atrioventricular heart block, and an echocardiogram reveals a large pericardial effusion. Both his heart block and pericardial effusion resolve by his first follow-up visit. Which of the following statements is true concerning long-term (secondary) prophylaxis against recurrent attacks of RF in this patient?

A: Long-term prophylaxis is not needed for this patient since he does not have evidence of rheumatic heart valve disease.
B: This patient should receive prophylaxis until aged 21 years.
C: This patient should receive prophylaxis for 10 years or well into adulthood, whichever is longer.
D: This patient should receive prophylaxis for 10 years since his last episode and at least until aged 40 years.
E: Lifelong prophylaxis is recommended for this patient.

The correct answer is C: Recommended by the World Health Organization, parenteral benzathine penicillin G (1.2 million U every 3-4 wk) is the most effective method for chemoprophylaxis against recurrences of RF. American Heart Association guidelines recommend that patients with RF without carditis receive prophylaxis for 5 years or until they are aged 21 years, whichever is longer. Patients such as this 16-year-old boy, who have RF with carditis but without residual heart disease (ie, no valve disease), should receive prophylaxis for 10 years or well into adulthood, whichever is longer. Patients who have RF with residual heart disease (persistent valvular disease based upon clinical or echocardiographic evidence) should receive prophylaxis for at least 10 years since the last episode and at least until they are aged 40 years. Sometimes lifelong prophylaxis is needed in these patients.

Pearl Question 1 (T/F): First-degree atrioventricular block is a specific finding in patients with rheumatic heart disease.

The correct answer is False: Carditis is the most serious complication of acute rheumatic fever and the second most common (50%). The mitral valve is the most common valve affected (65-75%) followed by the aortic valve, tricuspid valve and, rarely, the pulmonary valve. Other findings (eg, pericardial effusions, pericarditis, arrhythmias, CHF) may occur. First-degree atrioventricular block (prolonged PR interval), although often cited as a minor manifestation as part of the Jones criteria, is a nonspecific finding and should not be used as a major diagnostic criterion for the diagnosis of rheumatic heart disease.

Pearl Question 2 (T/F): A patient with acute rheumatic fever, rheumatic heart disease, and congestive heart failure that have failed to respond to medical management may benefit from open heart surgery.

The correct answer is True: Although cardiac surgery is most commonly performed in adults with mitral or aortic stenosis from chronic disease, it may be lifesaving when performed in children with acute disease and severe mitral or aortic insufficiency that is unresponsive to medical management.

Pearl Question 3 (T/F): The Carey Coombs murmur (heard in patients with severe acute rheumatic heart disease) is an apical systolic rub caused by pericardial inflammation.

The correct answer is False: The most common heart murmurs associated with acute rheumatic fever with cardiac involvement include a pansystolic murmur at the apex from mitral regurgitation, a diastolic murmur at the left upper sternal border from aortic insufficiency, and occasionally an apical diastolic murmur (Carey Coombs murmur) from relative mitral stenosis. The latter murmur occurs when mitral regurgitation is severe and is related to an excessive volume of flow across the mitral valve during inflow (normal pulmonary venous return plus regurgitant flow). A pericardial friction rub typically has both systolic and diastolic components.

Pearl Question 4 (T/F): The diagnosis of rheumatic fever may be excluded if no history of a recent pharyngeal infection exists.

The correct answer is False: History of antecedent sore throat (1-5 wk prior to onset) is extremely variable with the patient’s age. Older children and young adults give a history of sore throat in 70% of the incidents of rheumatic fever, while only 20% of younger children can recall an antecedent sore throat. Thus, rheumatic fever cannot be excluded based on the absence of antecedent sore throat.

BIBLIOGRAPHY

Section 10 of 10

• Abernethy M, Bass N, Sharpe N, et al: Doppler echocardiography and the early diagnosis of carditis in acute rheumatic fever. Aust N Z J Med 1994 Oct; 24(5): 530-5[Medline].
• Asbahr FR, Garvey MA, Snider LA, et al: Obsessive-compulsive symptoms among patients with Sydenham chorea. Biol Psychiatry 2005 May 1; 57(9): 1073-6[Medline].
• Carapetis JR, McDonald M, Wilson NJ: Acute rheumatic fever. Lancet 2005 Jul 9-15; 366(9480): 155-68[Medline].
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• Cotran RS, Kumar V, Collins T: Rheumatic fever. In: Robbins Pathologic Basis of Disease. 6th ed. WB Saunders Co; 1999: 570-73.
• Dajani A, Taubert K, Ferrieri P, et al: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American. Pediatrics 1995 Oct; 96(4 Pt 1): 758-64[Medline].
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• Guidelines for the diagnosis of rheumatic fever: Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Asso. JAMA 1992 Oct 21; 268(15): 2069-73[Medline].
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• Karademir S, OGuz D, Senocak F, et al: Tolmetin and salicylate therapy in acute rheumatic fever: Comparison of clinical efficacy and side-effects. Pediatr Int 2003 Dec; 45(6): 676-9[Medline].
• Massell BF, Fyler DC, Roy SB: The clinical picture of rheumatic fever. Diagnosis, immediate prognosis, course and therapeutic implications. Am J Cardiol 1958; 1: 436-39.
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• Pickering LK: Rheumatic Fever. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2000.
• Robertson KA, Volmink JA, Mayosi BM: Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc Disord 2005 May 31; 5(1): 11[Medline].
• Swedo SE, Leonard HL, Garvey M, et al: A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Am J Psychiatry 1998 Nov; 155(11): 1592-8[Medline].
• Veasy LG, Wiedmeier SE, Orsmond GS, et al: Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med 1987 Feb 19; 316(8): 421-7[Medline].
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