eMedicine Specialties > Infectious Diseases > Cardiovascular and Intravascular Infections

Rheumatic Fever

Mark Raymond Wallace, MD, Infectious Disease Fellowship Director, Orlando Regional Healthcare; Clinical Professor of Medicine, Florida State University
Larry I Lutwick, MD, Professor of Medicine, State University of New York, Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus; Jayashree Ravishankar, MD, Fellow, Department of Medicine, Division of Infectious Diseases, State University of New York Health Science Center at Brooklyn

Updated: Apr 13, 2009

Introduction

Background

Acute rheumatic fever (ARF) is an autoimmune inflammatory process that develops as a sequela of streptococcal infection. ARF has extremely variable manifestations and remains a clinical syndrome for which no specific diagnostic test exists. Persons who have experienced an episode of ARF are predisposed to recurrence following subsequent (rheumatogenic) group A streptococcal infections. The most significant complication of ARF is rheumatic heart disease, which usually occurs after repeated bouts of acute illness.

Pathophysiology

ARF is characterized by nonsuppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system. An extensive literature search has shown that, at least in developed countries, rheumatic fever follows pharyngeal infection with rheumatogenic group A streptococci.^1,2,3,4 The risk of developing rheumatic fever after an episode of streptococcal pharyngitis has been estimated at 0.3-3%.¹ More recent investigations of rheumatic fever occurring in the aboriginal populations of Australia suggest that streptococcal skin infections might also be associated with the development of rheumatic fever.^5,6 In Oceania and Hawaii, streptococcal strains that are not typically associated with rheumatic fever have been found to cause the disease.⁷

Molecular mimicry accounts for the tissue injury that occurs in rheumatic fever. Both the humoral and cellular host defenses of a genetically vulnerable host are involved. In this process, the patient's immune responses (both B- and T-cell mediated) are unable to distinguish between the invading microbe and certain host tissues.⁸ The resultant inflammation may persist well beyond the acute infection and produces the protean manifestations of rheumatic fever.

Frequency

United States

The incidence of ARF has declined markedly in the past 50 years in both the United States and Western Europe. Most Western physicians see only the late sequelae of rheumatic heart disease; the diagnosis of an acute case is usually reason enough for a ground rounds presentation. This remarkable decline of rheumatic fever likely reflects improved socioeconomic conditions, as well the decline in prevalence of the classically described rheumatogenic strains of group A streptococci.

Following two decades of almost total absence, a resurgence of ARF occurred in the 1980s among middle-class white children in Salt Lake City, Utah.⁹ Clusters were also reported in US Army and Navy training camps during the same period.¹⁰ These limited outbreaks were associated with mucoid rheumatogenic strains that were rarely seen in the preceding 20 years. Today, ARF remains a rarity in most of the United States, although Hawaii and American Samoa continue to see a significant number of cases, many of which are caused by streptococcal strains not usually associated with rheumatic fever in persons of Polynesian descent.^7,11

International

In developing countries, the magnitude of ARF is enormous. Recent estimates suggest that 15.6 million people worldwide have rheumatic heart disease and that 470,000 new cases of rheumatic fever (approximately 60% of whom will develop rheumatic heart disease) occur annually, with 230,000 deaths resulting from its complications. Almost all of this toll occurs in the developing world.^12,13 The incidence rate of rheumatic fever is as high as 50 cases per 100,000 children in many areas. Areas of hyperendemicity (eg, indigenous populations of Australia and New Zealand) see an incidence of 300-500 cases per 100,000 children, while the rates are approximately 50-fold lower in their nonindigenous compatriots.⁶ Rheumatic fever in the 21st century appears to be largely a disease of crowding and poverty.

Mortality/Morbidity

Cardiac involvement is the most serious complication of rheumatic fever and causes significant morbidity and mortality. As stated above, about 60% of the approximately 470,000 patients diagnosed with ARF annually eventually develop carditis, joining the approximately 15 million worldwide with rheumatic heart disease. Those with rheumatic heart disease are at a high risk for additional cardiac damage with subsequent bouts of ARF and require secondary prophylaxis. Morbidity due to congestive heart failure (CHF), strokes, and endocarditis is common among individuals with rheumatic heart disease, and about 1.5% of persons with rheumatic carditis die of the disease annually.^12,6

Race

ARF is predominantly a disease of developing countries and is concentrated in areas of deprivation and crowding. It is rampant in the Middle East, in sub-Saharan Africa, in the Indian subcontinent, in certain areas of South America, in Polynesia, and among the indigenous populations of Australia and New Zealand. Although a genetic predisposition to ARF clearly exists,¹ the disease does not seem to have a major racial predisposition, as it was once common in the United States and Europe and seems to decline in any locale where living conditions improve.

Sex

Rheumatic fever does not have a clear-cut sexual predilection, although certain clinical manifestations, such as mitral stenosis and Sydenham chorea, are more common in females who have gone through puberty.

Age

ARF is most common among children aged 5-15 years. It is relatively rare in infants and uncommon in preschool-aged children. ARF occurs in young adults, but the incidence of first episodes of ARF falls steadily after adolescence and is rare after age 35 years.⁶ The lower rate of ARF in adults may represent a decreased risk of streptococcal pharyngitis in this cohort. Recurrent episodes, with their predisposition to cause or exacerbate valvular damage, occur until middle age.

Clinical

History

Rheumatic fever manifests as various signs and symptoms that may occur alone or in various combinations.

• Sore throat: Although estimates vary, only 35%-60% of patients with rheumatic fever recall having any upper respiratory symptoms in the preceding several weeks. Many symptomatic individuals do not seek medical attention, go undiagnosed, or do not take the prescribed antibiotic for acute rheumatic fever (ARF) prevention.^6,10
• Polyarthritis: Overall, arthritis occurs in approximately 75% of first attacks of ARF. The likelihood increases with the age of the patient, and arthritis is a major manifestation of ARF in 92% of adults.¹⁰
  • The arthritis of ARF is usually symmetrical and involves large joints, such as the knees, ankles, elbows, and wrists. Tenosynovitis is common in adults and may be severe enough to suggest a diagnosis of disseminated gonococcal disease.¹⁰
  • The evolution of arthritis in individual joints tends to overlap; therefore, multiple joints may be inflamed simultaneously, causing more of an additive than a migratory pattern.¹⁰
  • In most instances, the entire bout of polyarthritis subsides within 4 weeks without any permanent damage. If not, a different diagnosis should be entertained.
• Carditis: Of first attacks of ARF, carditis occurs in 30%-60% of cases. It is more common in younger children but does occur in adults.¹⁰
  • Severe inflammation can cause congestive heart failure (CHF).
  • Patients with carditis may present with shortness of breath, dyspnea upon exertion, cough, paroxysmal nocturnal dyspnea, chest pain, and/or orthopnea. Carditis may also be asymptomatic and may be diagnosed solely by auscultation or, perhaps, echocardiography (controversial; see Physical).⁶
• Sydenham chorea: This occurs in up to 25% of ARF cases in children but is very rare in adults. It is more common in girls. Sydenham chorea in ARF is likely due to molecular mimicry, with autoantibodies reacting with brain ganglioside.¹⁴
  • Sydenham chorea may occur with other symptoms or as an isolated finding. It typically presents 1-6 months after the precipitating streptococcal infection and usually has both neurologic and psychological features.¹⁴
  • In the isolated form, laboratory evidence of a preceding streptococcal infection may be lacking.
  • Like the polyarthritis, Sydenham chorea usually resolves without permanent damage but occasionally lasts 2-3 years and be a major problem for the patient and her family.⁶
• Erythema marginatum: In first attacks of ARF in children, erythema marginatum occurs in approximately 10%. Like chorea, it is very rare in adults.
  • Patients or parents may report a nonpruritic, painless, serpiginous, erythematous eruption on the trunk. It is usually noted only in fair–skinned patients.²
  • The lesions may persist intermittently for weeks to months.
• Subcutaneous nodules are rarely noticed by the patient (see Physical).
• Other symptoms may include fever, abdominal pain, arthralgia, malaise, and epistaxis.

Physical

• Polyarthritis
  • Joint involvement in ARF may range from arthralgia to frank polyarthritis characterized by swelling, redness, warmth, and joint tenderness.
  • The joints frequently involved include the knees, ankles, elbows, and wrists. The small joints of the hands and the spine are rarely involved. Hand involvement tends to occur in poststreptococcal arthritis, a related syndrome without a risk of carditis.⁶
  • Inflammation begins to subside within a few days to a week and disappears within 2-4 weeks.
  • The arthritis is classically described as migratory, but, in many cases, new joints are affected before the previously involved joints improve, leaving the appearance of an additive arthritis.¹⁰
  • In most cases, the process does not leave any residual damage. On very rare occasions, periarticular fibrosis occurs after rheumatic arthritis, the so-called Jaccoud joint.
• Carditis
  • Carditis is the only manifestation of ARF with significant potential to cause long-term disability and/or death. It is usually a pancarditis involving the pericardium, myocardium, and endocardium.
  • The signs of carditis include the development of new murmurs, cardiac enlargement, CHF, pericardial friction rub, and/or pericardial effusion.
  • Characteristic murmurs of acute carditis include the high-pitched, blowing, holosystolic, apical murmur of mitral regurgitation; the low-pitched, apical, mid-diastolic, flow murmur (Carey-Coombs murmur); and a high-pitched, decrescendo, diastolic murmur of aortic regurgitation heard at the aortic area. Murmurs of mitral and aortic stenosis are observed in chronic valvular heart disease. Isolated aortic disease is distinctly unusual.
  • The features of CHF include tachycardia, a third heart sound, rales, and edema.
  • Pericarditis presents as a pericardial rub or effusion.
  • The use of echocardiography to detect subclinical carditis reveals subclinical rheumatic cardiac disease (both acute and chronic) not appreciated by the standard examination.^15,16,17 Whether these subclinical carditis findings carry the same clinical importance as those detected by standard auscultation is unclear; echocardiography findings alone do not currently count toward fulfillment of the Jones criteria, and it is unclear whether they necessitate secondary antibiotic prophylaxis (see Diagnosis). This issue is the most contentious in the rheumatic fever literature^18,19 and has major implications for diagnosis and screening. For now, clinicians must rely on their best judgment when evaluating possible carditis detected only with echocardiography.
• Subcutaneous nodules
  • Subcutaneous nodules are uncommon and are usually associated with severe carditis. They tend to occur several weeks after illness onset, are usually painless, and usually go unnoticed by the patient.
  • They are found primarily over the bony surfaces or prominences and in tendon sheaths. The common sites include the elbows, knees, wrists, ankles, over the Achilles tendon, the back of the scalp, and spinous process of the vertebrae.²
  • They usually persist for 1-2 weeks. The main differential diagnosis includes primarily the nodules of rheumatoid arthritis.¹⁰
• Erythema marginatum
  • The individual lesions of erythema marginatum are evanescent, moving over the skin in serpiginous patterns. Likened to smoke rings, they have a tendency to advance at the margins while clearing in the center.
  • The lesions may be macular and can develop and disappear in minutes, appearing to change shape while being examined.
  • They are found on the trunk and proximal aspects of the extremities and often go unnoticed by patients and parents, as they are usually covered by clothing.²
• Sydenham chorea
  • This is a neurological disorder characterized by emotional lability, personality change, muscular weakness, and uncoordinated, involuntary, purposeless movements.
  • The classic weakness is characterized by the inability to sustain a tetanic contraction. Patients are unable to maintain a clenched fist when attempting to grip the examiner's hand. Other findings include dysarthric speech, gait problems, and poor fine-motor skills.¹⁴
  • The motor symptoms usually disappear during sleep and may be partially suppressed by sedation.
  • They can involve the face, hands, and feet.
• The average duration of an untreated ARF attack is 3 months. Chronic rheumatic fever, generally defined as disease persisting for longer than 6 months, occurs in less than 5% of cases.

Causes

• Group A beta-hemolytic streptococcal infection may lead to rheumatic fever. The overall attack rate after streptococcal pharyngitis 0.3-3%, but certain genetically predisposed individuals, comprising perhaps 3%-6% of the population, account for those who develop rheumatic fever.⁶
• Studies in developed countries have established that rheumatic fever followed only pharyngeal infections and that not all serotypes of group A streptococci cause rheumatic fever. For example, some strains (eg, M types 4, 2, 12) in a population susceptible to rheumatic disease do not result in recurrences of rheumatic fever. The classic rheumatogenic serotypes are thought to include 3, 5, 6, 14, 18, 19, and 24.² More recent data, largely from studies of the indigenous peoples of Australia, suggest that skin infections (pyoderma) can predispose to ARF and that various other serotypes may be involved.^6,5
• Two basic theories have been postulated to explain the development of ARF and its sequelae following group A streptococcal infection: (1) a toxic effect produced by an extracellular toxin of group A streptococci on target organs such as the myocardium, valves, synovium, and brain and (2) an abnormal immune response to streptococcal components. Increasing and compelling evidence now strongly favors the autoimmune explanation. It seems clear that an exaggerated immune response in a susceptible individual leads to rheumatic fever. This probably occurs through molecular mimicry, in which the immune response fails to differentiate between epitopes of the streptococcal pathogen and certain host tissues.^6,8

Differential Diagnoses

Other Problems to Be Considered

Gout
Bacterial endocarditis
Disseminated gonococcal infection
Systemic vasculitis
Acute hepatitis B or C
Poststreptococcal arthritis
Still disease
Arthralgias and elevated antistreptolysin-O (ASO) titers²⁰
Sarcoidosis

Workup

Laboratory Studies

• No single specific laboratory test can confirm the diagnosis of acute rheumatic fever (ARF). Evidence of preceding group A streptococcal infection is an integral part of the Jones criteria for ARF diagnosis unless the patient has chorea (which may occur months after the inciting infection) or indolent rheumatic heart disease (see Diagnosis).⁶
• Throat culture remains the criterion standard for confirmation of group A streptococcal infection. Rapid antigen detection tests are not as sensitive.
  • If a rapid antigen detection test result is negative, obtain a throat culture in patients with suspected rheumatic fever.
  • On the other hand, because of the high specificity of these tests, a positive rapid antigen test confirms a streptococcal infection.
• Antibody titer tests used include ASO test, antistreptococcal DNAse B (ADB) test, and the antistreptococcal hyaluronidase (AH) test.
  • ASO is a test used to detect streptococcal antibodies directed against streptococcal lysin O. An elevated titer is proof of a previous streptococcal infection. It is usually more elevated after a pharyngeal than skin infection, while the ADB is typically elevated regardless of the site of the infection.²¹
  • Acute and convalescent sera, if available, are helpful for proving recent streptococcal infection.
  • The antibody tests must be interpreted with caution in areas with high rates of streptococcal infection and ARF, as relatively high titers are commonly encountered in the population. These tests are of greater utility in areas with lower prevalence (eg, in most Western countries).²²
• Acute-phase reactants, the erythrocyte sedimentation rate (ESR), and C-reactive protein levels (CRP) are usually elevated at the onset of ARF and serve as a minor manifestation in the Jones criteria. These tests are nonspecific, but they may be useful in monitoring disease activity.
• Blood cultures are obtained to help rule out infective endocarditis, bacteremia, and disseminated gonococcal infection.

Imaging Studies

• Chest radiography can reveal cardiomegaly and CHF in patients with carditis.
• Echocardiography may demonstrate valvular regurgitant lesions in patients with ARF who do not have clinical manifestations of carditis. This does not qualify as carditis in the most recent Jones diagnostic criteria, as the clinical implications of subclinical carditis remain unclear, but some experts believe the diagnostic criteria for ARF should be modified to allow for specific abnormalities found only on echocardiograms to be included. This is a controversial topic (see Physical).^{17,16,15,18,19}
  • Valvular stenotic lesions, especially of the mitral valve, can be observed in rheumatic heart disease.
  • In the absence of mitral valve disease involvement, isolated echocardiographic disease of the aortic valve is uncommon in patients with rheumatic heart disease.

Other Tests

• The most common finding on electrocardiography is a prolongation of the PR interval, which is a nonspecific finding, but counts as a minor manifestation in the Jones diagnostic criteria. It does not count as proof of carditis.
  • On rare occasions, second- or third-degree heart block is present.
  • In patients with chronic rheumatic heart disease, electrocardiography may show left atrial enlargement secondary to mitral stenosis.
• Various other studies may be needed to rule out other illnesses in the differential diagnoses. Common tests would include rheumatoid factor, antinuclear antibody (ANA), Lyme serology, blood cultures, and evaluation for gonorrhea.

Procedures

• Arthrocentesis can be performed to rule out septic arthritis but is usually unnecessary.

Histologic Findings

Rheumatic fever is characterized pathologically by exudative and proliferative inflammatory lesions of the connective tissue in the heart, joints, blood vessels, and subcutaneous tissue.

In the early stage, fragmentation of collagen fibers, cellular infiltration that is predominantly lymphocytic, and fibrinoid deposition followed by the appearance of a myocardial Aschoff nodule (a perivascular focus of inflammation that has an area of central necrosis surrounded by a rosette of large mononuclear and giant multinuclear cells) occur. The nuclei of these cells resemble owl eyes and are called Anichkov cells.

Subcutaneous nodules histologically resemble Aschoff nodules. The brain may show scattered areas of arteritis and petechial hemorrhages, which have an uncertain relationship to Sydenham chorea.

Diagnosis

Because acute rheumatic fever (ARF) can have diverse manifestations and because no specific diagnostic test for the disease exists, arriving at the correct diagnosis is particularly important. This is essential not only in terms of prescribing appropriate therapy for the acute attack but also because of the necessity for prescribing continuous antistreptococcal prophylaxis to prevent subsequent attacks and additional damage.

The Jones criteria were first established in 1944 and have been modified or updated several times, most recently in 1992. In general, the changes have tended to make the criteria more specific and less sensitive. This makes sense in the developed world, where the incidence of ARF continues to fall, but cases may be missed in high-prevalence areas. The main controversies now center around the use of echocardiography alone to confirm carditis (currently not allowed) and the need to show evidence of a current or recent streptococcal infection (with exceptions for chorea and indolent rheumatic heart disease).^6,19,18 If echocardiography alone were adequate for confirmation of carditis and the requirement for proof of prior streptococcal infection dropped, the Jones criteria would be much more inclusive but less specific.²³

• Major criteria
  • Carditis (based on clinical criteria)
  • Polyarthritis
  • Chorea (rare in adults)
  • Erythema marginatum (uncommon; rare in adults)
  • Subcutaneous nodules (uncommon; rare in adults)
• Minor criteria
  • Arthralgia (cannot count arthritis as a major criterion and arthralgia as a minor criterion)
  • Fever
  • Elevated ESR or CRP level
  • Prolonged PR interval

Evidence of group A streptococcal disease is required except when rheumatic fever is first discovered after a long latent period (eg, Sydenham chorea, indolent carditis).

• Evidence of preceding group A streptococcal infection - Positive throat culture or rapid antigen test result
• Elevated or rising streptococcal antibody titer

If supported by evidence of preceding group A streptococcal infection, the presence of two major manifestations or one major and two minor manifestations indicates a high probability of ARF. Failure to fulfill the Jones criteria makes the diagnosis unlikely but not impossible. Clinical judgment is required.

The World Health Organization (WHO) follows the Jones criteria for the diagnosis of ARF, but possible recurrences require only two minor criteria plus evidence of recent streptococcal infection.⁶

Treatment

Medical Care

Management and prevention of acute rheumatic fever (ARF) can be divided into the following 4 approaches:

• Treatment of the group A streptococcal infection that led to the disease: Although never proven to improve the one-year outcome, this is a standard practice.^6,1 It may at least serve to reduce the spread of rheumatogenic strains.
• General treatment of the acute episode
  • Anti-inflammatory agents are used to control the arthritis, fever, and other acute symptoms. Salicylates are the preferred agents, although other nonsteroidal agents are probably equally efficacious. Steroids are also effective but should probably be reserved for patients in whom salicylates fail. None of these anti-inflammatory agents has been shown to reduce the risk of subsequent rheumatic heart disease.
  • Bed rest is a traditional part of ARF therapy and is especially important in those with carditis. Patients are typically advised to rest through the acute illness and to then gradually increase activity; some clinicians monitor the patient’s ESR and restart activity only as it normalizes.^6,1
  • Intravenous immunoglobulin has not been shown to reduce the risk of rheumatic heart disease or to substantially improve the clinical course.²⁴
  • Chorea is usually managed conservatively in a quiet nonstimulatory environment; valproic acid is the preferred agent if sedation is needed. Intravenous immunoglobulin, steroids, and plasmapheresis have all been used successfully in refractory chorea, although conclusive evidence of their efficacy is limited.^6,14
• Cardiac management: Bed rest is essential in patients with cardiac involvement. Carditis resulting in heart failure is treated with conventional measures; some use corticosteroids for severe carditis, although data to support this are scant.⁶ Diuretics are the mainstay of therapy. Monitor for development of arrhythmias in patients with active myocarditis.
• Penicillin prophylaxis (see Medication)

Surgical Care

Surgical care is not typically indicated in ARF. Surgical intervention is required only to treat long-term valvular cardiac sequelae of ARF that cause stenosis.

Consultations

• Consultation with a cardiologist may be required to manage heart blocks and CHF.
• Consultation with a neurologist or psychiatrist may be required to confirm the diagnosis of chorea and to assist in its management.
• Consultations with an infectious disease specialist and rheumatologist may be helpful in diagnosis.

Diet

No specific dietary recommendation exists. CHF may require salt restriction.

Activity

Bed rest is a time-honored part of ARF therapy and is especially important in those with carditis. Patients are typically advised to rest through the acute illness and to then gradually increase activity; some clinicians monitor the ESR and restart activity only as it normalizes.^6,1

Medication

Antibiotics

Antibiotic treatment in patients who present with acute rheumatic fever (ARF) is necessary irrespective of the throat culture result. Such therapy probably does not alter the risk of developing rheumatic heart disease but at least minimizes the possible transmission of a rheumatogenic streptococcal strain.¹

Primary prophylaxis (treatment of streptococcal pharyngitis) dramatically reduces the risk of ARF and should be provided whenever a group A streptococcal pharyngitis is confirmed.

Secondary prevention is required to prevent additional streptococcal infections and is the critical step in management of ARF. Patients with a history of rheumatic fever are at a high risk of recurrent ARF, which may further the cardiac damage. The exact duration of chronic antimicrobial prophylaxis remains controversial, but the WHO guidelines are commonly used.¹ There had been concern that sustained benzathine penicillin as secondary prophylaxis would lead to the development of resistant strains of Streptococcus viridans, but a recent study found no support for this hypothesis.²⁵

Rheumatic fever with carditis and clinically significant residual heart disease requires antibiotic treatment for a minimum of 10 years after the latest episode; prophylaxis is required until the patient is aged at least 40-45 years and is often continued for life.

Rheumatic fever with carditis and no residual heart disease aside from mild mitral regurgitation requires antibiotic treatment for 10 years or until age 25 years (whichever is longer).

Rheumatic fever without carditis requires antibiotic treatment for 5 years or until the patient is aged 18-21 years (whichever is longer).

Children given penicillin G benzathine at a dose of 1.2 million U IM q4wk experienced a recurrence rate of 0.4 cases per 100 patient-years of observation. ARF recurrence rates have been found to be even lower if penicillin is administered q3wk instead of q4wk. This regimen may be appropriate in patients with severe rheumatic heart disease. Weigh the benefits of a 3-week regimen against patient compliance and cost. Long-term administration of oral penicillin may be used in lieu of the intramuscular route. Erythromycin or sulfadiazine may be used in patients who are allergic to penicillin.^6,1

Penicillin G benzathine (Bicillin L-A)

Long-acting depot form of penicillin G. DOC for prophylaxis of streptococcal pharyngitis. Avoids compliance problems of oral regimens.

Dosing

Adult

Primary prophylaxis (treatment of group A streptococcal pharyngitis): 1.2 million U IM once
Secondary prophylaxis: 1.2 million U IM q3-4wk

Pediatric

Primary prophylaxis (<27 kg): 600,000 U IM once
Secondary prophylaxis: 600,000 U IM q3-4wk

Interactions

Probenecid decreases clearance, causing increased penicillin effect; tetracyclines are bacteriostatic, possibly decreasing the effectiveness of penicillin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution if abnormal renal function, adjust dose accordingly

Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K, Robicillin VK, V-Cillin K)

Phenoxymethyl derivative of penicillin G is acid-stable, enhancing oral bioavailability. Patient compliance is essential for effectiveness.

Dosing

Adult

Primary prophylaxis (treatment of streptococcal pharyngitis): 500 mg PO bid/tid for 10 d
Secondary prophylaxis: 250 mg PO bid

Pediatric

Primary prophylaxis: 250 mg PO bid/tid for 10 d
Secondary prophylaxis:
<5 years: 125 mg PO bid
>5 years: 250 mg PO bid

Interactions

Probenecid decreases clearance, causing increased penicillin effect; tetracyclines are bacteriostatic, possibly decreasing effectiveness of penicillins

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal impairment, adjust dose accordingly

Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin, E-Mycin)

Macrolides inhibit protein synthesis, in contrast to penicillin cell wall effects. DOC for primary treatment of streptococcal pharyngitis in penicillin allergy. May use for secondary prophylaxis in patients allergic to penicillin.

Dosing

Adult

Primary prophylaxis: 250 mg erythromycin stearate, base, or estolate salts (or 400 mg ethylsuccinate) q6h PO or 500 mg PO q12h for 10 d; not to exceed 1 g/d; alternatively, 333 mg (as the base) q8h
Secondary prophylaxis: 250 mg PO bid

Pediatric

Primary prophylaxis: 30-50 mg/kg/d (base or ethylsuccinate) PO divided q6-8h; not to exceed 1 g/d
Secondary prophylaxis (base or ethylsuccinate):
<5 years: 125 mg PO bid
>5 years: 250 mg PO bid

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; inhibits CYP1A2 CYP3A4 isoenzymes

Contraindications

Documented hypersensitivity; hepatic impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in liver disease, estolate formulation may cause cholestatic jaundice; GI adverse effects are common; discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Sulfadiazine (Microsulfon)

Exerts bacteriostatic action through competitive antagonism with para-aminobenzoic acid (PABA). Microorganisms that require exogenous folic acid and do not synthesize folic acid are not susceptible to the action of sulfonamides. Used in secondary prophylaxis of ARF.

Dosing

Adult

1 g PO qd

Pediatric

<27 kg: 500 mg PO qd
>27 kg: 1 g/d PO

Interactions

Increases effect of oral anticoagulants and oral hypoglycemic agents; PABA or PABA metabolites of drugs (eg, tetracaine, sunscreens, procaine) decrease sulfadiazine effect

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in impaired renal/hepatic function (adjust dose); G-6-PD deficiency

Anti-inflammatory agents

Salicylates and corticosteroids are the mainstay of the anti-inflammatory treatment of ARF. Avoid anti-inflammatory drugs until diagnosis is confirmed, as they may mask symptoms essential to the diagnosis. Analgesics without anti-inflammatory properties (ie, codeine) are used for mild disease. Corticosteroids and salicylates cannot prevent or modify the development of subsequent rheumatic heart disease but are used for symptomatic relief. Some experts believe steroids are of value in patients with severe or fulminant carditis, but data are sparse.⁶

Clinical or laboratory manifestations of rheumatic inflammation may recur upon cessation of anti-inflammatory therapy. Rebound occurs frequently with corticosteroids; hence, they require gradual tapering rather than abrupt cessation. Salicylates are usually continued for a month following corticosteroid discontinuance.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Used in patients with moderate-to-severe arthritis and carditis without heart failure. Treatment is administered for at least 8 wk.

Dosing

Adult

90-100 mg/kg/d PO divided q6-8h for 2 wk initially, then 60-70 mg/kg/d for 6 wk; not to exceed 3.6-5.4 g/d

Pediatric

60-90 mg/kg/d PO divided q6-8h for 8 wk; adjust according to serum levels

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; serum levels of 20-30 mg/100 dL are required to control inflammatory response; high doses may cause gastric irritation or salicylate toxicity (ie, serum levels >20 mg/100 dL) and require dose reduction or alternative treatment with corticosteroids

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid with severe anemia, blood coagulation defects, or anticoagulants; relative contraindications include hepatic dysfunction, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, and asthma; due to association of aspirin with Reye syndrome, do not use in children (<16 y) who have influenza or varicella

Prednisone (Deltasone, Liquid-Pred, Meticorten, Orasone, Sterapred)

Used in severe carditis and CHF. High-dose prednisone is administered for 2-3 wk, then tapered over 3 wk. IV corticosteroids are reserved for fulminant cases.

Dosing

Adult

40-60 mg PO qd for 2-3 wk initially, then discontinue by gradual taper over 3 wk

Pediatric

0.05-2 mg/kg PO qd for 2-3 wk initially, then discontinue by gradual taper over 3 wk

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 (adjust dose); hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; significant hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; may cause hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections

Follow-up

Further Inpatient Care

• Most patients with acute rheumatic fever (ARF) can be treated at home.
• Inpatient care may be appropriate when the patient has severe constitutional symptoms, chorea, carditis with CHF, or major toxicity with the anti-inflammatory drugs.

Further Outpatient Care

Patients should be closely observed until all acute symptoms have resolved and they have returned to their normal state of health. Secondary prophylaxis requires years of follow-up and is the critical step in maintaining the health of the recovered patient (see Medication).

Inpatient & Outpatient Medications

• Patients with ARF need prolonged antibiotic prophylaxis to prevent recurrent attacks (see Medication).
• The anti-inflammatory drugs are not usually required for more than 4-8 weeks.

Deterrence/Prevention

Primary prophylaxis (treatment of streptococcal pharyngitis) dramatically reduces the risk of ARF and should be provided whenever possible. Secondary prophylaxis is essential in all patients with rheumatic fever (see Medication).

Ultimately, a vaccine will be the prevention of choice for ARF. Research on such a product is ongoing.²⁶

Complications

• Immediate complications
  • Pancarditis that causes CHF, heart blocks, or pericardial effusion requires emergent inpatient care and cardiology evaluation.
  • Chorea can present months after the inciting infection and can be quite debilitating.¹⁴
• Long-term sequelae
  • The only long-term sequela is rheumatic heart disease, which can present years later as valvular stenosis, most commonly involving the mitral valve. These patients are prone to infective endocarditis and stroke.
  • Valvular stenosis can lead to heart failure and may require surgery.

Prognosis

• The prognosis of ARF has been improved greatly by preventing recurrent attacks with secondary antimicrobial prophylaxis. The ultimate prognosis of an individual attack is related directly to the severity of cardiac involvement during the acute phase.
• About 60% of patients with carditis improve over a decade; in some, murmurs disappear. However, the overall prognosis is worse in those with severe carditis at first presentation,⁶ and most develop significant rheumatic heart disease.
• Only 6% of patients without carditis (or questionable carditis) during their attack of ARF have an audible heart murmur in 10 years.

Patient Education

• Patients, especially children, should receive medical attention when they develop a sore throat. Compliance with oral primary prophylaxis ("strep throat" treatment) and secondary prophylaxis regimens is essential to prevent ARF and its sequelae.

Miscellaneous

Medicolegal Pitfalls

• Diagnostic pitfalls
  • Because the diagnostic scheme for acute rheumatic fever (ARF) is based on a combination of signs and symptoms that may be caused by many other processes, be cautious when diagnosing a patient with ARF. This is particularly true in adults and in areas of low incidence.
  • Be aware that flares of ARF with myocarditis may occur years after the initial episode and can be confused with complications of rheumatic valvulopathy.
• Therapeutic pitfalls
  • Because of the potential for long-term valvular problems, even if the diagnosis of ARF is in doubt, consider beginning rheumatic fever prophylaxis as outlined above.
  • Although once-monthly intramuscular benzathine penicillin has been used for many years, breakthroughs during the final week have been reported, and a regimen of every 3 weeks may be preferable in those with severe rheumatic heart disease or breakthrough episodes (see Medication).
  • Determine the duration of prophylaxis into adulthood based on the patient's potential exposure to carriers of streptococcal infection (children). For example, an elementary school teacher would need longer prophylaxis than a lighthouse keeper.

References

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2. Stollerman GH. Rheumatic fever. Lancet. Mar 29 1997;349(9056):935-42. [Medline].

3. Bisno AL, Pearce IA, Stollerman GH. Streptococcal infections that fail to cause recurrences of rheumatic fever. J Infect Dis. Aug 1977;136(2):278-85. [Medline].

4. Shulman ST. Rheumatic heart disease in developing countries. N Engl J Med. Nov 15 2007;357(20):2089; author reply 2089. [Medline].

5. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat?. Lancet Infect Dis. Apr 2004;4(4):240-5. [Medline].

6. Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet. 2005;366:155-68. [Medline].

7. Erdem G, Mizumoto C, Esaki D, Reddy V, Kurahara D, Yamaga K, et al. Group A streptococcal isolates temporally associated with acute rheumatic fever in Hawaii: differences from the continental United States. Clin Infect Dis. Aug 1 2007;45(3):e20-4. [Medline].

8. Guilherme L, Kalil J, Cunningham M. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity. Feb 2006;39(1):31-9. [Medline].

9. Veasy LG, Wiedmeier SE, Orsmond GS. Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med. Feb 19 1987;316(8):421-7. [Medline].

10. Wallace MR, Garst PD, Papadimos TJ, Oldfield EC 3rd. The return of acute rheumatic fever in young adults. JAMA. Nov 10 1989;262(18):2557-61. [Medline].

11. Erdem G, Dodd A, Tuua A, Sinclair S, I'atala TF, Marrone JR, et al. Acute rheumatic fever in American Samoa. Pediatr Infect Dis J. Dec 2007;26(12):1158-9. [Medline].

12. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. Nov 2005;5(11):685-94. [Medline].

13. Carapetis JR. Rheumatic heart disease in developing countries. N Engl J Med. Aug 2 2007;357(5):439-41. [Medline].

14. Weiner SG, Normandin PA. Sydenham chorea: a case report and review of the literature. Pediatr Emerg Care. Jan 2007;23(1):20-4. [Medline].

15. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med. Aug 2 2007;357(5):470-6. [Medline].

16. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Sidi D, et al. Echocardiographic screening for rheumatic heart disease. Bull World Health Organ. Feb 2008;86(2):84. [Medline].

17. Vijayalakshmi IB, Vishnuprabhu RO, Chitra N, Rajasri R, Anuradha TV. The efficacy of echocardiographic criterions for the diagnosis of carditis in acute rheumatic fever. Cardiol Young. Oct 10 2008;1-7. [Medline].

18. Narula J, Kaplan EL. Echocardiographic diagnosis of rheumatic fever. Lancet. Dec 8 2001;358(9297):2000. [Medline].

19. Tubridy-Clark M, Carapetis JR. Subclinical carditis in rheumatic fever: a systematic review. Int J Cardiol. Jun 25 2007;119(1):54-8. [Medline].

20. Lopez-Benitez JM, Miller LC, Schaller JG, Moreno LM, de Canata ME. Erroneous diagnoses in children referred with acute rheumatic fever. Pediatr Infect Dis J. Feb 2008;27(2):181-2. [Medline].

21. Kaplan EL, Anthony BF, Chapman SS, Ayoub EM, Wannamaker LW. The influence of the site of infection on the immune response to group A streptococci. J Clin Invest. Jul 1970;49(7):1405-14. [Medline].

22. Ayoub EM, Nelson B, Shulman ST, Barrett DJ, Campbell JD, Armstrong G. Group A streptococcal antibodies in subjects with or without rheumatic fever in areas with high or low incidences of rheumatic fever. Clin Diagn Lab Immunol. Sep 2003;10(5):886-90. [Medline].

23. Pereira BA, da Silva NA, Andrade LE, Lima FS, Gurian FC, de Almeida Netto JC. Jones criteria and underdiagnosis of rheumatic fever. Indian J Pediatr. Feb 2007;74(2):117-21. [Medline].

24. Voss LM, Wilson NJ, Neutze JM, Whitlock RM, Ameratunga RV, Cairns LM. Intravenous immunoglobulin in acute rheumatic fever: a randomized controlled trial. Circulation. Jan 23 2001;103(3):401-6. [Medline].

25. Bilavsky E, Eliahou R, Keller N, Yarden-Bilavsky H, Harel L, Amir J. Effect of benzathine penicillin treatment on antibiotic susceptibility of viridans streptococci in oral flora of patients receiving secondary prophylaxis after rheumatic fever. J Infect. Apr 2008;56(4):244-8. [Medline].

26. Dale JB. Current status of group A streptococcal vaccine development. Adv Exp Med Biol. 2008;609:53-63. [Medline].

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Keywords

rheumatic fever, acute rheumatic fever, ARF, rheumatic heart disease, RHD, group A streptococcal pharyngitis, streptococcal pharyngitis, group A streptococci, group A Streptococcus, group A beta-hemolytic Streptococcus, group A beta-hemolytic streptococci, Duckett Jones criteria, Duckett-Jones criteria

Contributor Information and Disclosures

Author

Mark Raymond Wallace, MD, Infectious Disease Fellowship Director, Orlando Regional Healthcare; Clinical Professor of Medicine, Florida State University
Mark Raymond Wallace, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Tropical Medicine and Hygiene, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Larry I Lutwick, MD, Professor of Medicine, State University of New York, Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus
Larry I Lutwick, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Jayashree Ravishankar, MD, Fellow, Department of Medicine, Division of Infectious Diseases, State University of New York Health Science Center at Brooklyn
Jayashree Ravishankar, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Thomas J Marrie, MD, Chair, Professor, Department of Medicine, Division of Infectious Diseases, University of Alberta College of Medicine
Thomas J Marrie, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, Canadian Infectious Disease Society, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Richard B Brown, MD, FACP, Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine
Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and Massachusetts Medical Society
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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