Infectious Disease and Microbiology – Rheumatic Fever

Rheumatic fever is an inflammatory clinical syndrome that develops following infection of the pharynx with group A Streptococcus. It can produce a wide range of manifestations, including migratory arthritis, characteristic skin lesions, Sydenham chorea, and pancarditis with cardiac valvular dysfunction.

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Rheumatic fever occurs worldwide but has become relatively uncommon in developed countries because of improved living conditions and appropriate antibiotic treatment of streptococcal pharyngitis. It remains an important cause of acquired heart disease in developing countries, historically accounting for approximately 40% of heart disease in some populations. The estimated incidence in the United States has been approximately 0.5 per 100,000 population, with a prevalence of about 2 per 10,000. It primarily affects children between 6 and 15 years of age.

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Approximately one-third of cases may follow subacute or clinically unrecognized group A streptococcal pharyngitis. Historically, the attack rate after untreated streptococcal pharyngitis has ranged from approximately 0.4–3%. Outbreaks may be influenced by the particular circulating strains of Streptococcus.

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Important risk factors include overcrowded living conditions and a previous history of rheumatic fever. Genetic susceptibility has also been proposed, with associations involving certain HLA types, B-cell alloantigens, and immune-response gene polymorphisms, although the precise genetic contribution remains incompletely understood.

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Prevention begins with appropriate diagnosis and treatment of group A streptococcal pharyngitis. A complete course of penicillin therapy can prevent the development of rheumatic fever even when treatment is initiated several days after the onset of sore throat. Patients with a previous episode of rheumatic fever have a substantial risk of recurrence and therefore require secondary antibiotic prophylaxis. Benzathine penicillin G administered intramuscularly at regular intervals is a commonly used regimen, with oral penicillin or certain alternative antibiotics used when appropriate.

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The pathogenesis of rheumatic fever is primarily immune mediated. Molecular mimicry between antigens of group A Streptococcus and human tissues produces an abnormal immune response in which antibodies and immune cells directed against streptococcal components cross-react with host tissues, particularly structures within the heart.

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Group A streptococcal pharyngitis initiates the disease. Rheumatic fever typically develops approximately 1–5 weeks after the infection, with an average interval historically reported at about 19 days. Certain streptococcal strains have been particularly associated with rheumatic fever. Cross-reacting immune responses against streptococcal antigens and cardiac tissues, especially heart valves, contribute to the development of carditis.

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Patients may present with fever, fatigue, joint pain, skin manifestations, involuntary movements, dyspnea, or peripheral edema. Rheumatic fever is fundamentally a clinical diagnosis. Traditionally, diagnosis is based on the Jones criteria together with evidence of a preceding group A streptococcal infection. The clinical manifestations may persist for several months, particularly when carditis is present.

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The major clinical manifestations include migratory polyarthritis, carditis, Sydenham chorea, subcutaneous nodules, and erythema marginatum. Historically, polyarthritis has occurred in approximately 75% of cases, carditis in about 50%, chorea in approximately 15%, and subcutaneous nodules and erythema marginatum in fewer than 10%.

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Polyarthritis commonly occurs early in the disease and is frequently accompanied by fever. The arthritis predominantly involves large joints, particularly the knees, ankles, elbows, and wrists. Several joints may become involved sequentially, producing the characteristic migratory pattern. Joint manifestations generally resolve without permanent damage.

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Carditis may involve the endocardium, myocardium, and pericardium, producing pancarditis. Some cases are clinically subtle, whereas severe disease may present with congestive heart failure. Acute valvular involvement most commonly produces mitral regurgitation, followed by aortic regurgitation. Persistent valvular damage can eventually result in chronic rheumatic heart disease.

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Sydenham chorea consists of irregular, involuntary, purposeless, dance-like movements involving the face and extremities. It may occur together with arthritis and carditis or occasionally appear as the predominant manifestation of rheumatic fever.

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Subcutaneous nodules are painless lesions that usually develop over tendons or near joints. They may reach approximately 2 cm in diameter and are particularly associated with rheumatic carditis.

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Erythema marginatum is an uncommon, transient rash consisting of irregular erythematous lesions, usually involving the trunk and extremities. Because the lesions are evanescent, the rash may be difficult to detect during examination.

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Minor manifestations include fever and arthralgia without objective arthritis. Laboratory or electrocardiographic abnormalities contributing to the traditional minor criteria include elevated inflammatory markers such as erythrocyte sedimentation rate or C-reactive protein and prolongation of the PR interval on electrocardiography.

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Evidence of a preceding group A streptococcal infection should generally be established. This may include a positive throat culture, positive rapid streptococcal antigen testing, or elevated or rising streptococcal antibody titers such as antistreptolysin O, anti-DNase B, or antihyaluronidase antibodies. Exceptions may occur with manifestations such as Sydenham chorea or indolent carditis, which can appear sufficiently late that evidence of the original infection is difficult to demonstrate.

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Echocardiography is an important component of evaluation because it can detect valvular abnormalities and carditis that may not be obvious on physical examination. Serial echocardiography may be required when cardiac involvement progresses or when monitoring established carditis.

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Pathologically, rheumatic fever produces inflammatory lesions within connective tissues. Characteristic Aschoff bodies may be found in the myocardium. Cardiac inflammation can involve all layers of the heart, resulting in pancarditis.

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The differential diagnosis includes juvenile idiopathic arthritis, systemic lupus erythematosus, Lyme disease, gonococcal arthritis, infective endocarditis, viral infections such as rubella and coxsackievirus infection, medication reactions, sickle cell disease, sarcoidosis, inflammatory bowel disease, leukemia, and other causes of inflammatory arthritis or cardiac disease.

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Treatment is directed toward eradication of group A streptococcal infection, suppression of inflammation, management of cardiac complications, and prevention of recurrent disease. Anti-inflammatory therapy with aspirin or other appropriate anti-inflammatory agents has historically been used for arthritis and other inflammatory manifestations. Corticosteroids may be considered in severe carditis, particularly when significant heart failure is present.

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Older treatment regimens used high-dose aspirin, sometimes beginning at approximately 90–100 mg/kg/day and subsequently reducing the dose after clinical improvement. Corticosteroid therapy has historically been used for severe inflammatory cardiac disease. Because aspirin and corticosteroid regimens require careful consideration of toxicity and current clinical recommendations, treatment should be individualized and supervised appropriately.

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Secondary antibiotic prophylaxis is a central component of long-term management because recurrent streptococcal infections can cause additional episodes of rheumatic fever and progressively worsen valvular disease. The required duration depends on whether the initial episode involved carditis and whether residual valvular disease remains.

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Patients with rheumatic fever accompanied by carditis and persistent valvular disease generally require prolonged prophylaxis, historically for at least 10 years or until approximately 40 years of age, whichever is longer. Some individuals at continued high risk of streptococcal exposure or recurrent disease may require lifelong prophylaxis.

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When carditis occurred but no residual cardiac disease remains, prophylaxis has traditionally been continued for approximately 10 years or until at least 21 years of age, whichever period is longer. In rheumatic fever without carditis, prophylaxis is generally continued for at least 5 years or until approximately 21 years of age, whichever is longer. Sydenham chorea as a manifestation of rheumatic fever also warrants secondary prophylaxis.

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Severe valvular disease that fails medical management may require cardiothoracic surgical evaluation. Rheumatic heart disease remains an important indication for valve surgery in regions where rheumatic fever is common. Procedures may include mitral valve repair, commissurotomy, or valve replacement, depending on the type and severity of valvular damage.

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Hospitalization may be necessary for patients with significant carditis, heart failure, severe Sydenham chorea, or other serious manifestations. Discharge is generally appropriate when symptoms are adequately controlled and there is no evidence of uncontrolled heart failure.

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Patients with carditis require long-term clinical and echocardiographic follow-up, often involving both primary care and cardiology specialists. Education regarding adherence to secondary antibiotic prophylaxis is particularly important because recurrent attacks substantially increase the risk of permanent valvular damage.

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The overall prognosis depends largely on the severity of cardiac involvement and the occurrence of recurrent episodes. Many patients recover from the acute illness, but recurrence can occur following subsequent group A streptococcal infections, particularly when secondary prophylaxis is inadequate.

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The most important long-term complication is chronic rheumatic valvular heart disease. Progressive valve dysfunction can eventually result in refractory heart failure, arrhythmias, pulmonary hypertension, and the need for cardiac surgery. Patients with damaged valves may also have an increased risk of infective endocarditis.