A first episode of acute rheumatic fever (ARF) can occur at any age but occurs most often between 5 years and 15 years of age, which are the peak years of age for streptococcal pharyngitis. ARF is uncommon before 3 years and after 21 years. However, preceding symptomatic pharyngitis is recognized in only about two thirds of patients with ARF.
Worldwide, incidence ranges from 8 to 51/100,000 (1), with lowest rates (< 10/100,000) in North America and Western Europe and highest rates (> 10/100,000) in Eastern Europe, the Middle East, Asia, Africa, Australia, and New Zealand (2, 3, 4, 5). The attack rate (percentage of patients with untreated group A streptococcal pharyngitis who develop ARF) varies from < 1.0 to 3.0%. Higher attack rates occur with certain streptococcal M protein serotypes and a stronger host immune response (likely resulting from as-yet-uncharacterized genetic tendencies).
In patients with a prior episode of ARF, the rate of recurrence of ARF in untreated group A streptococcal pharyngitis approaches 50%, underscoring the importance of long-term antistreptococcal prophylaxis. Incidence has declined in most resource-rich countries but remains high in resource-poor parts of the world, especially parts with aboriginal or native populations, such as Alaskan Native, Canadian Inuit, Native American, Australian Aboriginal, and Maori New Zealander, where incidence is as high as 50 to 250/100,000. However, the continued occurrence in the United States of local outbreaks of ARF suggest that more rheumatogenic strains of streptococci are still present in the United States.
The prevalence of chronic rheumatic heart disease is uncertain because criteria are not standardized and autopsy is not done routinely, but it is estimated that worldwide there are ≥ 39 million patients with rheumatic heart disease, resulting in about 300,000 deaths annually.
Pearls & Pitfalls
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General references
1. Tibazarwa KB, Volmink JA, Mayosi BM: Incidence of acute rheumatic fever in the world: a systematic review of population-based studies. Heart 94(12):1534-1540, 2008. doi: 10.1136/hrt.2007.141309
2. Watkins DA, Johnson CO, Colquhoun SM, et al: Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med 377:713–722, 2017. doi: 10.1056/NEJMoa1603693
3. Carapetis JR, Beaton A, Cunningham MW, et al: Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 2:15084, 2016. doi: 10.1038/nrdp.2015.84
4. Sable C: Update on Prevention and Management of Rheumatic Heart Disease. Pediatr Clin North Am 67(5):843-853, 2020. doi: 10.1016/j.pcl.2020.06.003
5. Karthikeyan G, Guilherme L: Acute rheumatic fever. Lancet 392(10142):161-174, 2018. doi: 10.1016/S0140-6736(18)30999-1
Pathophysiology of Rheumatic Fever
Group A streptococcal (GAS) pharyngitis is the etiologic precursor of ARF, but host and environmental factors are important. GAS M proteins share epitopes (antigenic-determinant sites that are recognized by antibodies) with proteins found in synovium, heart muscle, and heart valve, suggesting that molecular mimicry by GAS antigens from rheumatogenic strains contributes to the arthritis, carditis, and valvular damage. Genetic host risk factors include the D8/17 B-cell antigen and certain class II histocompatibility antigens. Undernutrition, overcrowding, and lower socioeconomic status predispose to streptococcal infections and subsequent episodes of rheumatic fever.
Remarkably, although GAS infections of both the pharynx and of skin and soft-tissue structures, bones or joints, lungs, and bloodstream may cause poststreptococcal glomerulonephritis, nonpharyngitis GAS infections do not lead to ARF. The reason for this distinct difference in complications resulting from infection by the same organism is not well understood.
The joints, heart, skin, and central nervous system (CNS) are most often affected. Pathology varies by site.
Joints
Joint involvement manifests as nonspecific synovial inflammation, which if biopsied sometimes shows small foci resembling Aschoff bodies (granulomatous collections of leukocytes, myocytes, and interstitial collagen). Unlike the cardiac findings, however, the abnormalities of the joints are not chronic and do not leave scarring or residual abnormalities ("ARF licks the joints but bites the heart").
Heart
Cardiac involvement manifests as carditis, typically affecting the heart from the inside out, ie, valves and endocardium, then myocardium, and finally pericardium. It is sometimes followed years to decades later by chronic rheumatic heart disease, primarily manifested by valvular stenosis, but also sometimes by regurgitation, arrhythmias, and ventricular dysfunction.
In acute rheumatic fever, Aschoff bodies often develop in the myocardium and other parts of the heart. Fibrinous nonspecific pericarditis, sometimes with effusion, occurs only in patients with endocardial inflammation and usually subsides without permanent damage. Characteristic and potentially dangerous valve changes may occur. Acute interstitial valvulitis may cause valvular edema.
In chronic rheumatic heart disease, valve thickening, fusion, and retraction or other destruction of leaflets and cusps may occur, leading to stenosis or insufficiency. Similarly, chordae tendineae can shorten, thicken, or fuse, worsening regurgitation of damaged valves or causing regurgitation of an otherwise unaffected valve. Dilation of valve rings may also cause regurgitation.
Rheumatic valvular disease most commonly involves the mitral and aortic valves. The tricuspid and pulmonic valves are seldom if ever affected in isolation.
In acute rheumatic fever, the most common cardiac manifestations are
Mitral regurgitation
Pericarditis
Sometimes aortic regurgitation
In chronic rheumatic heart disease, the most common cardiac manifestations are
Mitral stenosis
Aortic regurgitation (often with some degree of stenosis)
Perhaps tricuspid regurgitation (often along with mitral stenosis)
Skin
Subcutaneous nodules appear indistinguishable from those of juvenile idiopathic arthritis (JIA), but biopsy shows features resembling Aschoff bodies.
Erythema marginatum differs histologically from other skin lesions with similar macroscopic appearance, eg, the rash of systemic JIA, immunoglobulin A–associated vasculitis (formerly called Henoch-Schönlein purpura), erythema chronicum migrans, and erythema multiforme.
Perivascular neutrophilic and mononuclear infiltrates of the dermis occur.
CNS
Sydenham chorea, the form of chorea that occurs with ARF, manifests in the CNS as hyperperfusion and increased metabolism in the basal ganglia.
Increased levels of antineuronal antibodies have also been shown.
Symptoms and Signs of Rheumatic Fever
An initial episode of symptoms of rheumatic fever occurs typically about 2 to 3 weeks after the streptococcal infection. Manifestations typically involve some combination of the joints, heart, skin, and CNS (1).
Joints
Migratory polyarthritis is the most common manifestation of ARF, occurring in about 35 to 66% of children; it is often accompanied by fever. "Migratory" means the arthritis appears in 1 or a few joints, resolves but then appears in others, thus seeming to move from 1 joint to another. Occasionally monarthritis occurs in high-risk indigenous populations (eg, in Australia, India, and Fiji) but very rarely in the United States. Joints become extremely painful and tender; these symptoms are often out of proportion to the modest warmth and swelling present on examination (this is in contrast to the arthritis of Lyme disease, in which the examination findings tend to be more severe than the symptoms).
Ankles, knees, elbows, and wrists are usually involved. Shoulders, hips, and small joints of the hands and feet also may be involved but almost never alone. If vertebral joints are affected, another disorder should be suspected.
Arthralgia-like symptoms may be due to nonspecific myalgia or tenodynia in the periarticular zone; tenosynovitis may develop at the site of muscle insertions. Joint pain and fever usually subside within 2 weeks and seldom last > 1 month.
Heart
Carditis can occur alone or in combination with pericardial rub, murmurs, cardiac enlargement, or heart failure. In the first episode of ARF, carditis occurs in about 50 to 70%. Patients may have high fever, chest pain, or both; tachycardia is common, especially during sleep. In about 50% of cases, cardiac damage (ie, persistent valve dysfunction) occurs much later.
Although the carditis of ARF is considered to be a pancarditis (involving the endocardium, myocardium, and pericardium), valvulitis is the most consistent feature of ARF, and if it is not present, the diagnosis should be reconsidered. The diagnosis of valvulitis has classically been made by auscultation of murmurs, but subclinical cases (ie, valvular dysfunction not manifested by murmurs but recognized on echocardiography and Doppler studies) may occur in up to 18% of cases of ARF.
Heart murmurs are common and, although usually evident early, may not be heard at initial examination; in such cases, repeated clinical examinations as well as echocardiography are recommended to determine the presence of carditis. Mitral regurgitation is characterized by an apical pansystolic blowing murmur radiating to the axilla. The soft diastolic blow at the left sternal border of aortic regurgitation, and the presystolic murmur of mitral stenosis, may be difficult to detect. Murmurs often persist indefinitely. If no worsening occurs during the next 2 to 3 weeks, new manifestations of carditis seldom follow. ARF typically does not cause chronic, smoldering carditis. Scars left by acute valvular damage may contract and change, and secondary hemodynamic difficulties may develop in the myocardium without persistence of acute inflammation.
Pericarditis may be manifested by chest pain and a pericardial rub.
Heart failure caused by the combination of carditis and valvular dysfunction may cause dyspnea without rales, nausea and vomiting, a right upper quadrant or epigastric ache, and a hacking, nonproductive cough. Marked lethargy and fatigue may be early manifestations of heart failure.
Skin
Cutaneous and subcutaneous features are uncommon and almost never occur alone, usually developing in a patient who already has carditis, arthritis, or chorea.
Subcutaneous nodules, which occur most frequently on the extensor surfaces of large joints (eg, knees, elbows, wrists), usually coexist with arthritis and carditis. Fewer than 10% of children with ARF have nodules. Ordinarily, the nodules are painless and transitory and respond to treatment of joint or heart inflammation.
Erythema marginatum is a serpiginous, flat or slightly raised, nonscarring, and painless rash. Fewer than 6% of children have this rash. The rash usually appears on the trunk and proximal extremities but not the face. It sometimes lasts < 1 day. Its appearance is often delayed after the inciting streptococcal infection; it may appear with or after the other manifestations of rheumatic inflammation.
CNS
Sydenham chorea occurs in about 10 to 30% of children. It may develop along with other manifestations but frequently arises after the other manifestations have subsided (often months after the acute streptococcal infection) and thus may be overlooked as an indicator of ARF. Onset of chorea is typically insidious and may be preceded by inappropriate laughing or crying. Chorea consists of rapid and irregular jerking movements that may begin in the hands but often becomes generalized, involving the feet and face.
Characteristic findings include fluctuating grip strength (milkmaid’s grip), tongue fasciculations or tongue darting (the tongue cannot protrude without darting in and out), facial grimacing, and explosive speech with or without tongue clucking. Associated motor symptoms include loss of fine motor control, and weakness and hypotonia (that can be severe enough to be mistaken for paralysis).
Previously undiagnosed obsessive-compulsive behavior may be unmasked in many patients.
Other
Fever (≥ 38.5° C) and other systemic manifestations such as anorexia and malaise can be prominent but are not specific. ARF can occasionally manifest as fever of unknown origin until a more identifiable sign develops.
Abdominal pain and anorexia can occur because of the hepatic involvement in heart failure or because of concomitant mesenteric adenitis, and rarely the situation may resemble acute appendicitis.
Recurrence
Recurrent episodes of ARF often mimic the initial episode; carditis tends to recur in patients who have had moderate to severe carditis in the past, and chorea without carditis recurs in patients who had chorea without carditis initially.
Symptoms and signs reference
1. Gewitz MH, Baltimore RS, Tani LY, et al: Revision of Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American Heart Association. Circulation 131:1806–1818, 2015. doi: 10.1161/CIR.0000000000000205
Diagnosis of Rheumatic Fever
Modified Jones criteria (for initial diagnosis)
Testing for group A streptococcal (GAS) infection (culture, rapid strep test, or antistreptolysin O and anti-DNase B titers)
ECG
Echocardiography with Doppler
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level
Diagnosis of a first episode of ARF is based on the modified Jones criteria (1) (see table Modified Jones Criteria for a First Episode of Acute Rheumatic Fever (ARF)*); 2 major criteria or 1 major criterion and 2 minor criteria are required, each along with evidence of preceding GAS infection. Sydenham chorea alone (ie, without minor criteria) fulfills diagnostic criteria if other causes of movement disorder are ruled out.
The modified Jones criteria were designed for the evaluation of ARF rather than for a possible recurrence. However, if patients have a reliable past history of ARF or rheumatic heart disease and also have documented GAS infection, the criteria may be used to establish the presence of a recurrence.
A preceding GAS infection is suggested by a recent history of pharyngitis and is confirmed by 1 or more of the following:
Positive throat culture
Increased or preferably rising antistreptolysin O titer
Positive rapid GAS antigen test in a child with clinical manifestations suggestive of streptococcal pharyngitis
Recent scarlet fever is highly suggestive. Throat cultures and rapid strep antigen tests are often negative by the time ARF manifests, whereas titers of antistreptolysin O and anti-DNase B typically peak 3 to 6 weeks after GAS pharyngitis. About 80% of children with ARF have a significantly elevated antistreptolysin O titer; if an anti-DNase B antibody level is also done, the percentage with confirmed GAS infection is higher, especially if acute and convalescent samples are tested.
Joint aspiration may be needed to exclude other causes of arthritis (eg, infection). The joint fluid is usually cloudy and yellow, with an elevated white blood cell (WBC) count composed primarily of neutrophils; culture is negative. Complement levels are usually normal or slightly decreased, compared with decreased levels in other inflammatory arthritides.
ECG is done during the initial evaluation. Serum cardiac marker levels are obtained; normal cardiac troponin I levels exclude prominent myocardial damage. ECG abnormalities such as PR prolongation do not correlate with other evidence of carditis. Only 35% of children with ARF have a prolonged PR interval; higher-degree heart block may occur but is uncommon. Other ECG abnormalities may be due to pericarditis, enlargement of ventricles or atria, or arrhythmias.
Echocardiography can detect evidence of carditis even in patients without apparent murmurs and is recommended for all patients with confirmed or suspected ARF. Echocardiography is also used to detect subclinical carditis in patients with apparently isolated Sydenham chorea and to monitor the status of patients with recurrences of carditis or chronic rheumatic heart disease. However, not all echocardiographic abnormalities represent rheumatic carditis; isolated trivial valvar regurgitation or trivial pericardial effusion may be a nonspecific finding. To maintain specificity, echocardiographic and Doppler results should meet the following criteria (1) for acute rheumatic carditis:
Doppler flow criteria:
Pathologic mitral regurgitation: Must be seen in at least 2 views, and have a jet length ≥ 2 cm in at least 1 view, a peak velocity of > 3 m/second, and a pansystolic jet in at least 1 envelope
Pathologic aortic regurgitation: Must be seen in at least 2 views, and have a jet length ≥ 1 cm in at least 1 view, a peak velocity of > 3 m/second, and a pandiastolic jet in at least 1 envelope
Echocardiographic morphologic criteria:
Pathologic mitral valve morphologic changes include annular dilation, chordal elongation or rupture with flail leaflet, anterior (or less commonly posterior) leaflet tip prolapse, or beading/nodularity of leaflet tips.
Pathologic aortic valve morphologic changes include irregular or focal leaflet thickening, coaptation defect, restricted leaflet motion, or leaflet prolapse.
Chest x-rays are not routinely done but can detect cardiomegaly, a common manifestation of carditis in ARF.
Biopsy of a subcutaneous nodule can aid in early diagnosis, especially when other major clinical manifestations are absent.
ESR and serum CRP are sensitive but not specific. The ESR is typically > 60 mm/hour. CRP is typically > 3 mg/dL (> 30 mg/L) and often > 7 mg/dL (> 70 mg/L); because it rises and falls faster than ESR, a normal CRP may confirm that inflammation is resolving in a patient with prolonged ESR elevation after acute symptoms have subsided. In the absence of carditis, ESR usually returns to normal within 3 months. Evidence of acute inflammation, including ESR, usually subsides within 5 months in uncomplicated carditis. The WBC count reaches 12,000 to 20,000/mcL (12 to 20 × 109/L) and may go higher with corticosteroid therapy.
The differential diagnosis includes JIA (especially systemic JIA and, less so, polyarticular JIA), Lyme disease, reactive arthritis, arthropathy of sickle cell disease, leukemia or other cancer, systemic lupus erythematosus, embolic bacterial endocarditis, serum sickness, Kawasaki disease, drug reactions, and gonococcal arthritis. These are frequently distinguished by history or specific laboratory tests. The absence of an antecedent GAS infection, the diurnal variation of the fever, evanescent rash, and prolonged symptomatic joint inflammation usually distinguish systemic JIA from ARF.
Modified Jones Criteria for a First Episode of Acute Rheumatic Fever (ARF)*
Manifestations | Specific Finding |
|---|---|
Major | Carditis† Chorea Erythema marginatum Polyarthritis Subcutaneous nodules |
Minor | Polyarthralgia‡ Elevated erythrocyte sedimentation rate (> 60 mm/hour) or C-reactive protein (> 30 mg/L [> 285.7 nmol/L]) Fever (≥ 38.5° C) Prolonged PR interval (on ECG)§ |
* Diagnosis of ARF requires 2 major or 1 major and 2 minor manifestations and evidence of group A streptococcal infection (elevated or rising antistreptococcal antibody titer [eg, antistreptolysin O, anti-DNase B], positive throat culture, or positive rapid antigen test in a child with clinical manifestations suggestive of streptococcal pharyngitis). | |
† Carditis can be clinical and/or subclinical. Subclinical carditis is defined by strict echocardiographic criteria. | |
‡ Polyarthralgia is not used for diagnosis if polyarthritis is a major criterion for the patient. | |
§ PR interval is adjusted for age and is not used for diagnosis if carditis is a major criterion for the patient. | |
Data from Gewitz MH, Baltimore RS, Tani LY, et al: Revision of Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American Heart Association. Circulation 131:1806–1818, 2015. doi: 10.1161/CIR.0000000000000205 | |
Diagnosis reference
1. Gewitz MH, Baltimore RS, Tani LY, et al: Revision of Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American Heart Association. Circulation 131:1806–1818, 2015. doi: 10.1161/CIR.0000000000000205
Treatment of Rheumatic Fever
Antibiotics
Aspirin
Sometimes corticosteroids
The primary goals of rheumatic fever treatment are eradication of group A streptococcal infection, relief of acute symptoms, suppression of inflammation, and prophylaxis against future infection to prevent recurrent heart disease.
For general management, patients should limit their activities if they have symptoms of arthritis, chorea, or heart failure. In the absence of carditis, no physical restrictions are needed after the initial episode subsides. In asymptomatic patients with carditis, strict bed rest has no proven value, despite its traditional usage.
The management of chronic cardiac valvular disease and heart failure is discussed elsewhere in THE MANUAL.
Antibiotic treatment
treatment of streptococcal pharyngitis. Antibiotic prophylaxis is continued as described below.
Aspirin and other anti-inflammatory medications
controls fever and pain and should be given to all patients with arthritis and/or mild carditis. Although aspirin has been used for many decades, there are surprisingly few data from controlled trials to define the optimal dosing schedule. Most experts would give children and adolescents 15 to 25 mg/kg orally 4 times a day (to a maximum daily dose of 4 to 6 g) for 2 to 4 weeks and then taper the dose over another 4 weeks. Symptomatic ARF responds dramatically to aspirinSalicylate toxicity is the limiting factor to aspirin therapy and is manifested by tinnitus, headache, or hyperpnea; it may not appear until after 1 week of therapy. Salicylate levels are measured only to manage toxicity. Enteric-coated, buffered, or complex salicylate molecules provide no advantage.
For patients with minimal to mild carditis, there are no controlled data to suggest that adding prednisone to aspirin therapy speeds resolution of illness or prevents rheumatic heart disease.
Other nonsteroidal anti-inflammatory drugs (NSAIDs)aspirin
is recommended instead of aspirinAspirin
Recurrences of mild cardiac inflammation (indicated by fever or chest pain) may subside spontaneously; aspirin or corticosteroids should be resumed if recurrent symptoms last longer than a few days or if heart failure is uncontrolled by standard management (eg, diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, inotropic agents).
Antibiotic prophylaxis
Antistreptococcal prophylaxis should be maintained continuously after the initial episode of ARF to prevent recurrences. Antibiotics taken orally are slightly less effective as those given by injection. However, with the oral route, painful injections are avoided, and clinic visits and observation for postinjection reactions are not needed.
The optimal duration of antistreptococcal prophylaxis is uncertain. Children without carditis should receive prophylaxis for 5 years or until age 21 (whichever is longer). The American Heart Association and the American Academy of Pediatrics both recommend that patients with carditis without evidence of residual heart damage receive prophylaxis for 10 years or until age 21 (whichever is longer) (1). Children with carditis and evidence of residual heart damage should receive prophylaxis for > 10 years; many experts recommend that such patients continue prophylaxis indefinitely or, alternatively, until age 40. Prophylaxis should be life long in all patients with severe valvular disease who have close contact with young children because young children have a high rate of GAS carriage.
The American Heart Association no longer recommends that patients with known or suspected rheumatic valvular disease take short-term antibiotic prophylaxis against bacterial endocarditis for dental or oral surgical procedures unless they have an indwelling prosthetic valve (see Prevention of Infective Endocarditis) (1).
Treatment reference
1. Gerber MA, Baltimore RS, Eaton CB, et al: Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 119(11):1541-1551, 2009. doi: 10.1161/CIRCULATIONAHA.109.191959
Prognosis for Rheumatic Fever
Prognosis following an initial episode of ARF depends mostly on how severely the heart is affected, and whether there is a recurrent episode of ARF. Murmurs eventually disappear in about half of patients whose acute episodes were manifested by mild carditis without major cardiac enlargement or decompensation. However, many others develop chronic valvular disease, including some who recovered from the acute episode without evidence of valvular disease.
Episodes of Sydenham chorea usually last several months and resolve completely in most patients, but about one third of patients have recurrences.
Joint inflammation may take 1 month to subside if not treated but does not lead to residual damage.
In patients with chronic valvular disease, symptoms develop and progress slowly, typically over several decades. However, once significant symptoms develop, intervention is usually necessary. In resource-poor countries, chronic rheumatic heart disease is the cause of 25 to 45% of all cardiovascular disease.
Key Points
Rheumatic fever is a nonsuppurative, acute, inflammatory complication of group A streptococcal (GAS) pharyngeal infection occurring most often initially between ages 5 years and 15 years.
Symptoms and signs may include migratory polyarthritis, carditis, subcutaneous nodules, erythema marginatum, and chorea.
Chronic rheumatic heart disease, particularly involving the mitral and/or aortic valves, may progress over decades and is a major cause of heart disease in resource-poor parts of the world.
Diagnosis of acute rheumatic fever (ARF) requires 2 major or 1 major and 2 minor manifestations (modified Jones criteria for a first episode of ARF) and evidence of GAS infection.
Give prophylactic antistreptococcal antibiotics after the initial episode of ARF to prevent recurrences.
Poststreptococcal Reactive Arthritis
Poststreptococcal reactive arthritis is development of arthritis after group A streptococcal infection in patients who do not meet the criteria for acute rheumatic fever.
Poststreptococcal reactive arthritis may or may not represent an attenuated variant of acute rheumatic fever (ARF). Patients do not have symptoms or signs of the carditis common in ARF.
Lyme arthritis, juvenile idiopathic arthritis) should be excluded.
Although clinical practice for secondary prevention of cardiac involvement varies greatly, it is reasonable to give antistreptococcal prophylaxis for several months to 1 year if ARF cannot be excluded, and then to reevaluate the patient. If cardiac lesions are detected by echocardiography, long-term prophylaxis is indicated.
