AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acute rheumatic fever (ARF) is an inflammatory process occurring as a delayed sequela to group A streptococcal pharyngitis due to certain group A streptococcal types. ARF is extremely variable in its manifestations and remains a clinical syndrome for which no specific diagnostic test exists. Persons who have experienced an episode of ARF are particularly predisposed to recurrent episodes following subsequent specific (rheumatogenic) types of group A streptococcal infections.

Pathophysiology

ARF is characterized by nonsuppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system that follow certain group A streptococcal upper respiratory infections. Only some or one manifestation may be present in an individual.

Frequency

United States

The overall incidence of ARF cannot be determined precisely because of the inherent difficulties in making the diagnosis, and most states no longer maintain rheumatic fever registries. However, the incidence of ARF has declined markedly in the 20th century in both the United States and Western Europe.

In military camps, the incidence of ARF after untreated streptococcal upper respiratory infections has been reported to be around 3% and less than 1% in civilians.

Traditionally, ARF has been a disease of lower socioeconomic groups; however, in the mid 1980s, a resurgence of ARF occurred in many middle class white communities in Salt Lake City, Utah. Small clusters also were reported in Ohio; Pennsylvania; and Nashville and Memphis, Tenn. Clusters also were reported in many army and navy training camps. The civilian outbreaks mostly occurred in white children.

International

In developing countries, the magnitude of the problem of ARF is enormous. It has been estimated that at least 50,000 episodes of ARF annually occur in India and more than 1 million patients with rheumatic heart disease (RHD) exist. A World Health Organization (WHO) survey conducted from 1986-1990 estimated the prevalence of ARF/RHD to be 12.6 cases per 1000 school children in Zambia, 10.2 cases per 1000 school children in Sudan, and 7.9 cases per 1000 school children in Bolivia.

Mortality/Morbidity

Cardiac involvement is the most serious complication and carries significant morbidity both acutely and chronically, with the mortality from ARF being higher in developing countries. Surveillance of ARF has been flawed by overreporting and underreporting because of diagnostic errors and failure to verify cases. In the United States, the surveillance has been discontinued in many states because of the cost and apparent low rate of the disease.

Race

ARF predominantly is a disease of developing countries. It is rampant in the Middle East, Indian subcontinent, and certain areas of South America. The major predisposing environmental condition identified is overcrowding. For that reason, the incidence is higher among blacks than whites.

Sex

No clear-cut sexual predilection exists, though certain clinical manifestations, such as mitral stenosis and Sydenham chorea, have a female preponderance after puberty.

Age

ARF is more common among children aged 6-15 years. It is relatively rare in infants and preschool-aged children. ARF may occur in adults, but the incidence of first episodes of ARF is much lower in adults than in adolescents. The lower rate of ARF in adults may represent a decreased risk of streptococcal pharyngitis in this cohort.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

• Sore throat: Only two thirds of patients remember having any upper respiratory symptoms in the past 1-5 weeks.
• Arthritis: Overall, arthritis occurs in approximately 75% of first attacks of ARF. The incidence varies with age. The proportion of cases with arthritis increases with the age of the patients, and arthritis is generally the primary manifestation in adults.
• • Arthritis in ARF classically is migratory. It usually involves large joints, such as the knees, ankles, elbows, and wrists.
  • The evolution of arthritis in individual joints tends to overlap; therefore, multiple joints may be inflamed at the same time.
  • In most instances, the entire bout of polyarthritis subsides within 4 weeks.
• Carditis: Of first attacks of ARF, carditis occurs in 40-50% of cases. It is more common in younger children and may be asymptomatic in mild cases.
• • Severe inflammation can cause the clinical picture of congestive heart failure (CHF).
  • Patients may present with shortness of breath, dyspnea on exertion, cough, paroxysmal nocturnal dyspnea, and orthopnea.
• Sydenham chorea: This occurs in nearly 15% of first attacks of ARF.
• • It may occur with other symptoms or as an isolated form.
  • In the isolated form, laboratory evidence of a preceding streptococcal infection may be lacking.
• Erythema marginatum: Of the first attacks of ARF, erythema marginatum occurs in 10%.
• • Patients report a nonpruritic, nonpainful, erythematous eruption on the trunk that may be evanescent.
  • The lesions may persist intermittently for weeks to months.
• Other symptoms may include fever, abdominal pain, arthralgia, and epistaxis.

Physical

• Polyarthritis
• • Joint involvement in ARF may range from arthralgia to frank arthritis characterized by swelling, redness, warmth, and tenderness of the joints.
  • The joints frequently involved are the knees, ankles, elbows, and wrists. The small joints of the hands and the spine rarely are involved.
  • Inflammation begins to subside within a few days to a week and disappears within 2-3 weeks.
  • Classically migratory, 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 the significant potential to cause long-term disability and/or death. It usually is a pancarditis involving the pericardium, myocardium, and endocardium.
  • The clinical signs of carditis include the development of new murmurs, cardiac enlargement, CHF, pericardial friction rub, or pericardial effusion.
  • Characteristic murmurs of acute carditis are 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 would be distinctly unusual.
  • The features of CHF are tachycardia, a third heart sound, and crepitations in the lung fields.
  • Pericarditis presents as a pericardial rub or effusion.
• Subcutaneous nodules
• • Subcutaneous nodules usually are associated with severe carditis and tend to occur several weeks after its onset.
  • They are found primarily over the bony surfaces or prominences and over tendons. The common sites are elbows, knees, wrists, ankles, over the Achilles tendon, and occiput or spinous process of the vertebrae.
  • They usually persist for 1-2 weeks.
• 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 to hours.
  • They are found on the trunk and proximal aspects of the extremities.
• Sydenham chorea
• • This is a neurological disorder characterized by emotional lability, muscular weakness, and rapid and uncoordinated involuntary purposeless movements.
  • They disappear during sleep and may be partially suppressed by sedation.
  • They can involve the face, hands, and feet.
• The average duration of an untreated attack is approximately 3 months. Chronic rheumatic fever, generally defined as disease persisting for longer than 6 months, occurs in less than 5% of cases.

Causes

• The group A beta-hemolytic streptococcus is the inciting agent leading to the development of ARF.
• • Not all of the serotypes of group A streptococci can cause rheumatic fever. As an example, when some strains (eg, M type 4) are present in a very susceptible rheumatic population, no recurrences of rheumatic fever ensue.
  • The rheumatogenic serotypes are thought to include 1, 3, 5, 6, 14, 18, 19, and 24.
• Two basic theories are postulated to explain the development of these sequelae following group A streptococcal pharyngitis.
• • A toxic effect produced by an extracellular toxin of group A streptococci on target organs such as the myocardium, valves, synovium, and brain
  • An abnormal immune response to streptococcal components by the human host
• The most popular hypotheses are those that postulate an abnormal immune response by the human host to some still-undefined component of group A streptococci. The resulting antibodies then might cause the immunologic damage leading to clinical manifestations.
• Although humans may have genetic differences in rheumatic susceptibility, the exact mechanism remains unknown. The pathogenetic mechanism for the development of rheumatic fever after upper respiratory tract infection with group A beta-hemolytic streptococci most likely involves a combination of specific characteristics of the organism and some incompletely defined genetic predisposition in the human host.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Gout
Subacute bacterial endocarditis
Disseminated gonococcal infection
Acute pyogenic arthritis
Systemic vasculitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No single specific laboratory test can confirm the diagnosis of ARF. Evidence of preceding group A streptococcal infection is a very integral part of the diagnosis.
• A throat culture remains the criterion standard for confirmation of the presence of group A streptococci.
• Rapid antigen detection tests have reduced sensitivity.
• • If a rapid antigen detection test result is negative, obtain a throat culture in patients with suspected rheumatic fever.
  • On the other hand, because the specificity of these tests is high, a positive result confirms a streptococcal infection.
• Antibody titer tests used include antistreptolysin-O (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 clearly is proof of a previous streptococcal infection, but a more reliable way of demonstrating the earlier infection is by showing a rise in titer between acute and convalescent sera.
  • The ASO test peaks in 3-6 weeks after infection, whereas the ADB test peaks in 6-8 weeks. If acute and convalescent sera are available, test simultaneously.
• Acute phase reactants, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), usually are elevated at the onset of ARF. These tests are nonspecific, but they are very useful in monitoring disease activity.
• Blood cultures are obtained to rule out infective endocarditis, bacteremia, and disseminated gonococcal infection.

Imaging Studies

• Chest x-ray can detect cardiomegaly and CHF in patients with carditis.
• Echocardiograms may demonstrate valvular regurgitations in patients with ARF who do not have clinical manifestations of carditis.
• • Valvular stenotic lesions, especially of the mitral valve, can be observed in RHD.
  • In the absence of mitral valve disease involvement, isolated echocardiographic disease of the aortic valve is very uncommon in patients with RHD.

Other Tests

• On electrocardiogram, the most common finding is a prolongation of the PR interval, which is a nonspecific finding.
• • On rare occasions, second- or third-degree heart block may be present.
  • In patients with chronic RHD, ECG may show left atrial enlargement secondary to mitral stenosis.

Procedures

• Arthrocentesis can be undertaken to rule out septic arthritis. It usually is not required.

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Because ARF can have diverse manifestations and no specific diagnostic test for the disease exists, arriving at the correct diagnosis is particularly important in ARF. This is essential not only in terms of prescribing appropriate therapy for the acute attack and formulating an accurate prognosis but also because of the necessity for prescribing continuous antistreptococcal prophylaxis to prevent subsequent attacks. The following Duckett Jones criteria are applied stringently for the diagnosis of ARF:

• Major criteria
• • Carditis
  • Polyarthritis
  • Chorea
  • Erythema marginatum
  • Subcutaneous nodules
• Minor criteria
• • Arthralgia
  • Fever
  • Elevated ESR or CRP
  • Prolonged PR interval
  • Evidence of preceding group A streptococcal infection–like from positive results on throat cultures or rapid antigen test
  • Elevated or rising streptococcal antibody titer
• If supported by evidence of preceding group A streptococcal infection, the presence of 2 major manifestations or 1 major and 2 minor manifestations indicates a high probability of ARF. Failure to fulfill the Jones criteria should make the diagnosis doubtful, except in situations in which rheumatic fever is first discovered after a long latent period, eg, Sydenham chorea or indolent carditis.

Surgical Care

Surgical care usually is not indicated in ARF. Surgical intervention is only required with the long-term sequelae of ARF, in which the heart valves are involved, causing stenosis.

Consultations

A consultation with a cardiologist is required to manage heart blocks and CHF. A consultation with a neurologist may be required to confirm the diagnosis when chorea is the only manifestation.

Diet

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

Activity

Bed rest is indicated for acute carditis with congestive cardiac failure. Prolonged bed rest usually is unnecessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Management of ARF can be divided into the following 3 approaches:

• Treatment of the group A streptococcal infection that led to the disease
• Anti-inflammatory agents to control the arthritis
• Supportive therapy, including management of congestive cardiac failure if it occurs

Carditis resulting in heart failure is treated by conventional measures. Diuretics are the mainstay of therapy. Monitor for development of cardiotonic-induced arrhythmias in patients with active myocarditis.

Development of chorea requires sedation and a quiet nonstimulatory environment. Severe debilitating hyperkinesis is treated with major tranquilizers. Plasmapheresis and intravenous immunoglobulin (IVIG) are investigational in intractable chorea.

Drug Category: Antibiotics

Primary prevention of patients presenting with ARF is necessary irrespective of the throat culture result. Antibiotic therapy does not alter the course of group A streptococcal infections, but it is administered to minimize possible transmission of a rheumatogenic streptococcal strain.

Secondary prevention is required to prevent intercurrent streptococcal infections. Patients with a history of rheumatic fever are at high risk of developing recurrent ARF. Optimal duration of chronic antimicrobial prophylaxis remains controversial.

Rheumatic fever with carditis and residual heart disease requires antibiotic treatment for a minimum of 10 years since the last episode; prophylaxis is required at least until the patient is aged 40 years and sometimes for life.

Rheumatic fever with carditis and no residual heart disease requires antibiotic treatment for 10 years or well into adulthood—whichever is longer.

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

Children administered 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 for patients with RHD. Weigh the benefits of a 3-wk regimen against patient compliance and cost. Long-term administration of oral penicillin may be used in lieu of IM.

Drug Category: Anti-inflammatory agents

Salicylates and corticosteroids are the mainstay of anti-inflammatory treatment of ARF. Avoid anti-inflammatory drugs until diagnosis is confirmed (they may mask symptoms essential to the diagnosis). Analgesics without anti-inflammatory properties (ie, codeine) are used for mild disease. Corticosteroids or salicylates cannot prevent or modify the development of subsequent RHD.

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 continued for a month following corticosteroid discontinuance.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Most patients can be managed at home.
• Inpatient care is appropriate when the patient has severe constitutional symptoms (in the presence of severe carditis with CHF) due to severe toxicity with the anti-inflammatory drugs.

In/Out Patient Meds

• Patients need prolonged antibiotic prophylaxis to prevent recurrent attacks (see Medication).
• The anti-inflammatory drugs are not required for more than 6 weeks.

Complications

• Immediate complications
• • Pancarditis causing either CHF, heart blocks, or pericardial effusion is an immediate complication.
  • Chorea can present late without the initial manifestations and can be debilitating.
• Long-term sequelae
• • The only long-term sequela is RHD, which can present years later as valvular stenosis commonly involving the mitral valve. These patients are prone to infective endocarditis and must take antibacterial prophylaxis for the indicated procedures.
  • Valvular stenosis can lead to heart failure and may require surgery.

Prognosis

• The prognosis in ARF has been improved greatly by preventing recurrent attacks with antimicrobial prophylaxis. The ultimate prognosis of an individual attack is related rather directly to the severity of cardiac involvement during the acute phase.
• About 6% of patients without carditis (or questionable carditis) during their attack of ARF can have a heart murmur in 10 years.
• Of patients with initial, apical, systolic murmur, 30% may have heart disease at follow-up. This increases to 40% if the patient had an initial basal diastolic murmur.
• Patients who initially experienced CHF or pericarditis have an approximate 70% chance of developing heart disease in 10 years.

Patient Education

• Patients, especially children, should seek immediate medical attention when they develop a sore throat.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Diagnostic pitfalls
• • Because the diagnosis of ARF is based on a combination of signs and symptoms that may be caused by other processes, especially when the complex is not a complete one, be cautious when labeling a patient as having ARF. This particularly is true in adults.
  • This can be an issue when obtaining health or life insurance later in life.
  • Be aware that flares of ARF with myocarditis may occur years after the initial episode, and they 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 the institution of rheumatic fever prophylaxis as outlined previously.
  • 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 is preferable.
  • Determine the duration of prophylaxis into adulthood based on the patient's potential exposure to streptococcal infection carriers in the form of children. For example, an elementary school teacher would need longer prophylaxis than a lighthouse keeper would.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bisno AL. Group A streptococcal infections and acute rheumatic fever. N Engl J Med. Sep 12 1991;325(11):783-93. [Medline].
• 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].
• Carapetis JR, Steer AC, Mulholland EK. The global burden of group A streptococcal disease. Lancet Infect Dis. 2005;5:685-94.
• Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet. 2005;366:155-68. [Medline].
• Feinstein AR, Spagnuolo M, Taranta A. Host factors in the susceptibility of rheumatic patients to streptococcal infections. Am J Epidemiol. Jul 1975;102(1):42-6. [Medline].
• Guiherme L, Kalil J, Cunningham M. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity. 2006;39:31-39.
• Hounie AG, Pauls DL, do Rosario-Campos MC. Obsessive-compulsive spectrum disorders and rheumatic fever: a family study. Biol Psychiatry. 2006;Apr 7:[in press].
• Nausieda PA, Grossman BJ, Koller WC. Sydenham chorea: an update. Neurology. Mar 1980;30(3):331-4. [Medline].
• Robertson KA, Volmink JA, Mayosi BM. Antibiotics for the primary prevention of acute rheumatic fever. BMC Cardiovasc Disorders. 2005;5:11.
• Spagnuolo M, Pasternack B, Taranta A. Risk of rheumatic-fever recurrences after streptococcal infections. Prospective study of clinical and social factors. N Engl J Med. Sep 16 1971;285(12):641-7. [Medline].
• Valkenburg HA, Haverkorn MJ, Goslings WR. Streptococcal pharyngitis in the general population. II. The attack rate of rheumatic fever and acute glomerulonephritis in patients. J Infect Dis. Oct 1971;124(4):348-58. [Medline].
• 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].

Article Last Updated: Jun 29, 2006