Rayji S. Tsutsui
Brian P. Griffin
I.Introduction. Rheumatic fever (RF) is a systemic autoimmune disorder related to prior streptococcal infection and is the leading cause of heart disease in those under the age of 40 years living in developing nations.
A.The incidence of RF and prevalence of rheumatic heart disease vary substantially among countries. In many developing countries, the incidence of acute RF approaches or exceeds 200 per 100,000, whereas in the Unites States, it is estimated to be less than 1 per 100,000. Since the first half of this 20th century, there has been a gradual decline in the incidence of RF in the United States. This is due to improved public health and living conditions, the development of modern antibiotics, as well as a shift in the endemic strains of group A streptococcus (GAS). Localized outbreaks of RF have occurred in the United States as recently as the mid-1980s.
B.RF is more common among populations at high risk for streptococcal pharyngitis, such as military recruits, those in close contact with school-aged children, and persons of low socioeconomic status. It most commonly occurs between the ages of 5 and 18 years. RF affects both sexes equally, except for Sydenham chorea, which is more prevalent in females after puberty.
C.With difference in incidence world wide, it has been recommended to risk stratify patients according to population risk at large in order to help tailor the index of suspicion. Low-risk populations are those with RF incidence ≤2 per 100,000 school-aged children or all-age rheumatic heart disease prevalence of ≤1 per 1,000 population per year such as the case with United States.
D.RF can present in a variable manner particularly in high-risk populations such as the indigenous Australian population. Those include aseptic monoarthritis and low-grade fever.
E.Echocardiography has become an integral part of RF diagnosis. Carditis is one of the major presentation of RF. Classically, it is diagnosed by auscultation of a murmur that is consistent with aortic or mitral valve regurgitation. Indeed, valvulitis remains the most common presentation of RF. With improvement in Doppler echocardiography, the concept of subclinical carditis has arisen, where a patient may have echocardiographic findings of typical valvular disease but may not have a typical murmur on auscultation or a murmur was missed on examination. This subclinical carditis group is thought to comprise approximately 17% of prevalent RF cases.
II.Clinical presentation. The clinical manifestations of RF develop 3 weeks after a GAS tonsillopharyngitis. It is important to note that one-third of patients with RF do not remember having had a sore throat. Patients with RF present initially with a sudden onset of constitutional symptoms, including fever (101°C to 104°C), malaise, weight loss, and pallor. An exudative and proliferative inflammatory process involving collagen fibrils characterizes the acute phase of RF. Multiple organ systems, such as the dermis, central nervous system, synovium, and heart, may be involved. In addition, manifestations may include serositis and involvement of the lungs, kidneys, and central nervous system.
A.Diagnostic criteria
1.The Jones criteria are designed to aid in the diagnosis of the first episode of RF. It can be diagnosed when a previous upper airway infection with GAS is detected in conjunction either with two major manifestations or with one major and two minor manifestations. Major manifestations include arthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules. Minor manifestations include fever, arthralgias, high C-reactive protein (CRP) level or high erythrocyte sedimentation rate (ESR), and a prolonged PR interval on electrocardiogram (ECG) (Table 20.1).
TABLE 20.1 Diagnosis of Rheumatic Fever |
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GAS Infection |
Major Jones Criteria |
Minor Jones Criteria |
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Culture |
Low Riska |
Moderate–High Risk |
Low Riska |
Moderate–High Risk |
ASO titers Anti-DNAse B Other antistreptococcal antibodies Streptococcal antigens |
Carditis (clinical or subclinicalb) Polyarthritis only Chorea Erythema marginatum Subcutaneous nodules |
Carditis (clinical or subclinicalb) Mono or polyarthritis, polyarthralgia Chorea Erythema marginatum Subcutaneous nodules |
Polyarthralgia Fever (≥38.5°C) ESR ≥ 60 mm in the first hour and/or CRP ≥ 3.0 mg/dL Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion) |
Monoarthralgia Fever (≥38°C) ESR ≥ 30 mm/h and/or CRP ≥ 3.0 mg/dL Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion) |
The diagnosis of rheumatic fever requires confirmation of a previous GAS infection with at least one of the methods listed above together with either two major criteria or one major criterion and two minor criteria.
ASO, antistreptolysin O; anti-DNase, antideoxyribonuclease B; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GAS, group A streptococcus.
aLow-risk populations are those with RF incidence ≤2 per 100,000 school-aged children or all-age rheumatic heart disease prevalence of ≤1 per 1,000 population per year.
bSubclinical carditis indicates echocardiographic valvulitis.
2.In some circumstances, the diagnosis of RF can be made without strict adherence to Jones criteria, as in cases of indolent or recurrent carditis or isolated cases of chorea when other causes have been excluded.
3.Echocardiography has become one of the cornerstones of RF diagnosis (i.e., carditis) in addition to the Jones criteria to allow for the diagnosis of subclinical carditis. A 2015 American Heart Association (AHA) statement recommends that echocardiography should be performed in all definite and suspected cases of RF and if evidence of carditis is not detected, it rules out the carditis diagnosis (Table 20.2).
TABLE 20.2 Doppler Findings in Rheumatic Valvulitis |
Pathologic Mitral Regurgitation (All Four Criteria Met) |
Seen in at least two views |
Jet length ≥2 cm in at least one view |
Peak velocity > 3 m/s |
Pan systolic jet in at least one envelope |
Pathologic Aortic Regurgitation (All Four Criteria Met) |
Seen in at least two views |
Jet length ≥ 1 cm in at least one view |
Peak velocity > 3 m/s |
Pan diastolic jet in at least one envelope |
From Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806–1818, with permission; American Heart Association, Inc.
B.Major manifestations (Table 20.1)
1.Carditis/subclinical carditis. This is the most serious and is often regarded as the most specific manifestation of RF, affecting 50% to 70% of patients. It may manifest as pancarditis affecting the endocardium, myocardium, and pericardium simultaneously.
a.Cardiac involvement ranges from an asymptomatic presentation to progressive congestive heart failure and death.
b.The most typical manifestations include tachycardia, arrhythmias, new murmurs or pericardial friction rub, cardiomegaly, and heart failure.
c.Heart failure is rare in the acute phase; if present, it is usually the result of myocarditis.
d.The most characteristic component of rheumatic carditis is a valvulitis (endocarditis) involving the mitral and aortic valves.
(1)Mitral regurgitation is the hallmark of rheumatic carditis. Aortic insufficiency is less common and is almost always associated with mitral insufficiency. As a rule of thumb, patients under the age of 30 years tend to present with isolated mitral regurgitation, whereas patients develop mitral stenosis during the third decade, with mixed mitral valve disease predominating thereafter.
(2)Subclinical carditis: No murmurs are heard but presence of valve thickening on echocardiography occurs in up to 17%.
(3)Acute mitral valve regurgitation produces an apical systolic murmur that may be accompanied by a mid-diastolic Carey Coombs murmur of relative mitral stenosis (a high-pitched early diastolic murmur that varies from day to day). Right-sided valves are rarely involved.
(4)Those valvular lesions that are diagnosed by echocardiogram but are clinically silent usually heal without scarring and have a good prognosis. Controversy exists whether echocardiographic findings of mitral regurgitation or aortic insufficiency constitute subclinical rheumatic carditis sufficient to meet the Jones criteria.
e.Pericarditis may cause chest pain, friction rubs, and distant heart sounds but is often clinically silent.
3.Sydenham chorea. Also known as Saint Vitus dance or chorea minor, this extrapyramidal disorder is characterized by purposeless and involuntary movements of face and limbs, muscular hypotonia, and emotional lability.
a.Initial manifestations include difficulty in writing, talking, or walking.
b.Sydenham chorea is a delayed manifestation of RF, usually appearing 3 months or more after an upper airway infection; it is often the sole manifestation of acute RF. Chorea has been reported in up to 30% of the patients. Most cases tend to follow a benign course, with complete resolution of symptoms in 2 to 3 months, although cases in which symptoms persisted for >2 years have been reported.
c.Differential include tics, athetosis, conversion reactions, hyperkinesia, and behavioral abnormalities.
4.Subcutaneous nodules. These usually measure 0.5 to 2 cm and are firm, painless, and freely mobile nodules that can be isolated or found in clusters over the extensor surfaces of joints (knees, elbows, and wrists), bony prominences, tendons, dorsum of foot, occipital region, and cervical processes. They are seen in up to 20% of patients with RF and last for a few days. The skin overlying the nodules is freely mobile and shows no signs of discoloration or inflammation.
5.Erythema marginatum. This is an evanescent erythematous macular rash with a pale center of irregular shape. It is usually nonpruritic and tends to disappear after a few days. It is highly specific, occurring in <5% of patients, and is obvious only in fair-skinned individuals. The lesions vary in size and do not typically affect the face. The rash may be induced by application of heat. Its presence is suggestive of coexisting carditis.
C.Minor manifestations. Fever and arthralgias are common, but nonspecific findings of RF can be used to support the diagnosis of RF when only a single major manifestation is present (Table 20.1).
1.Fever is encountered during the acute phase of the disease and does not follow a specific pattern.
2.Arthralgia is defined as pain in one or more large joints without objective findings of inflammation on physical examination.
3.Other clinical manifestations of RF include abdominal pain, epistaxis, acute glomerulonephritis, rheumatic pneumonitis, hematuria, and encephalitis. These are not included as diagnostic criteria for the diagnosis of RF.
III.Etiology and pathophysiology
A.The association between tonsillopharyngitis–scarlet fever epidemics and acute RF in the 1930s, the findings of high levels of antistreptolysin O (ASO) in sera of patients with RF, and the confirmation of antibiotics as an efficient mode of prophylaxis of RF provide strong evidence that GAS is the agent causing initial and recurrent attacks of RF.
1.Acute RF is likely caused by an immunologic mechanism. Specifically, it appears that patients who develop RF demonstrate a hyperimmune response to GAS, and the level of the immune response correlates with the severity of the RF manifestations. Supporting evidence includes onset approximately 3 weeks following an upper respiratory tract infection, rarity before the age of 5 years when the immune system is still immature, and cross-reactivity between streptococcal cellular antigens and proteins present in human connective tissue.
a.The most important antigenic structures (M, T, and R proteins) are localized in the external layer of the bacterial cell wall.
b.The M protein not only is responsible for type-specific immunity but also has a powerful antiphagocytic action and is classically regarded as a marker of streptococcal rheumatogenic potential. Patients with acute RF possess high levels of antibodies targeted against this protein. Specific M serotypes of GAS have long been recognized as strong stimulators of a robust immune response and are associated with an increased risk of developing RF. Those M serotypes associated with impetigo or pyoderma may cause glomerulonephritis but are not associated with RF.
2.In epidemics of streptococcal pharyngitis, it is estimated that approximately 3% of untreated individuals will go on to develop RF. However, recurrence of RF is seen in about 50% of patients with a history of RF. For endemic GAS pharyngeal infections, the incidence of RF is much less common.
B.Numerous epidemiologic studies favor a familial and even genetic predisposition. A monoclonal antibody to B-cell alloantigen (D8/17) is almost universally detected in patients with RF, whereas this antibody is present in <14% of the general population. In addition, susceptibility to RF has also been linked with D-related human leukocyte antigen 1, 2, 3, and 4 haplotypes. These genetic markers may be useful in the future to identify individuals susceptible to acute RF.
IV.Laboratory examination and diagnostic testing. RF is a clinical diagnosis because there is no single laboratory study that is diagnostic of RF.
A.Supporting evidence of antecedent GAS infection can be obtained through cultures, antigen test, or serum antistreptococcal antibody test.
1.Although no consensus exists regarding which tests to order at what time, commonly ASO titers and cultures are initially obtained when RF is suspected. Other tests (see below) are useful only under certain conditions.
2.A negative throat culture is usually sufficient to withhold antibiotic treatment in most cases, especially if clinical suspicion of RF is low.
3.Elevated or rising ASO titers provide solid evidence for recent GAS infection. A greater than twofold rise in ASO titers compared with convalescent titers is diagnostic.
4.The probability of detecting a previous GAS infection can be increased by obtaining repeated ASO tests or by looking for antibodies to other streptococcal antigens, such as antideoxyribonuclease B.
5.A slide agglutination test is commercially available, which measures antibodies to several streptococcal antigens. However, it is not well standardized and is not very reproducible. Therefore, it is not recommended as a definitive test.
B.Biopsies
1.Aschoff nodules, a form of granulomatous inflammation, can be seen in the proliferative stage and are considered pathognomonic for rheumatic carditis. They are encountered in 30% to 40% of biopsies from patients with primary or recurrent episodes of RF. Such nodules are most often found in the interventricular septum, the wall of the left ventricle, or the left atrial appendage.
2.The histologic findings of endocarditis include edema and cellular infiltration of valvular tissue. Hyaline degeneration of the affected valve results in the formation of verrucae at its edge, preventing the normal leaflet coaptation. If the inflammatory process persists, fibrosis and calcification develop, leading to valvular stenosis.
3.Endomyocardial biopsy does not help in diagnosing first attacks of rheumatic carditis. It is useful in distinguishing chronic inactive rheumatic heart disease from acute rheumatic carditis. As such, it is rarely indicated except in cases where recurrent carditis is suspected but cannot be confirmed otherwise.
1.As in any inflammatory process, leukocytosis, thrombocytosis, or hypochromic or normochromic anemia may be noted.
2.The favored tests to measure acute phase response are ESR and CRP. Although these tests are nonspecific, they may be helpful in monitoring the inflammatory activity of the disease. These levels are almost always elevated during the acute phase of RF in patients with arthritis and polyarthritis and are usually normal in patients with chorea.
D.Radiography. Chest radiography may identify increased cardiac size, increased pulmonary vasculature, or pulmonary edema.
E.Electrocardiography and echocardiography. In patients in whom carditis is subtle and signs of valvular involvement may be mild or transient, a baseline ECG may help provide evidence of carditis. Echocardiography should be performed in all cases of suspected RF.
1.The most common finding in the ECG is the presence of PR prolongation and sinus tachycardia. Myocarditis may prolong the QT interval. In cases of pericarditis, low-voltage QRS complexes and ST-segment changes in the precordial leads can be observed.
2.Echocardiography is likely to show mitral regurgitation or aortic insufficiency. Calcifications of the leaflets and subvalvular apparatus are present in the chronic, not acute, phase of rheumatic heart disease. Echocardiography/Doppler findings not consistent with carditis should be excluded in the diagnosis of a patient with a murmur. Transesophageal echocardiography should be considered if obtaining adequate images are difficult with transthoracic echocardiography particularly paying attention to the mitral and aortic valves.
V.Therapy. It is generally recommended that patients with suspected RF be admitted for close observation and workup.
A.Secondary prophylaxis with penicillin has been shown to reduce not only streptococcal infections but recurrent attacks of acute RF as well. Patients with mild carditis should receive secondary prophylaxis for 10 years after the most recent attack or at least until the age of 25 years, whichever is longer. More severe valvular damage necessitates lifelong secondary prophylaxis.
B.Congestive heart failure should be managed with standard therapy (Chapters 8 and 9).
C.Aspirin and salicylates have been the preferred treatment for the inflammatory manifestations of RF specifically for the arthritis. Aspirin has been traditionally used in a dose of 80 to 100 mg/kg/d given at 4 hourly aliquots in children, and a total of 4 to 8 g/d given in aliquots every 4 to 6 hours for adults. There is increasing experience with the use of NSAIDS and especially naproxen instead of aspirin in the treatment of arthritis which may lessen the risk of Reyes syndrome in children and can be given less frequently. The dose of naproxen used is 10 to 20 mg/kg/d divided in doses every 12 hours with a maximum dose of 1,000 mg in children older than 2 and maximal dose in adults of 1,250 mg. In patients with any degree of cardiac involvement, aspirin is preferred over corticosteroids as steroids may lead to fluid retention and worsen heart failure symptoms. Neither aspirin nor corticosteroids, despite relieving symptoms of inflammation, prevent valvular damage.
D.If intolerant to aspirin, the recommended dose of corticosteroid (prednisone) is 1 to 2 mg/kg/d (maximum of 60 mg/d). Salicylate or steroid therapy does not affect the course of carditis except perhaps in severe carditis where steroids may have a role though this is controversial; therefore, the duration of anti-inflammatory therapy is somewhat arbitrary and is guided by the severity of disease and the response to therapy. Therapy should be continued until there is sufficient clinical and laboratory evidence of disease inactivity. After cessation of anti-inflammatory agents, relapse with mild symptoms may occur. If using a steroid, a gradual reduction in steroid dosing is necessary to avoid relapses. If symptoms are mild, they usually subside without specific treatment. For severe symptoms, treatment with salicylates should be tried before restarting corticosteroids.
VI.Prevention. See Table 20.3.
TABLE 20.3 Prevention of Rheumatic Fever |
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Drug |
Dosage |
Route |
Duration |
|
Primary Prevention |
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Benzathine (penicillin G) |
600,000 U (≤27 kg) |
IM |
Once |
1.2 million U (≥27 kg) |
|||
or |
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Penicillin V (children) |
250 mg (2–3 times/d) |
Oral |
10 d |
Penicillin V (adolescents and adults) |
500 mg (2–3 times/d) |
Oral |
10 d |
|
Penicillin-allergic patients |
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Erythromycin ethyl succinate |
40 mg/kg/d (2–4 times/d up to 1 g/d) |
Oral |
10 d |
Erythromycin estolate |
20–40 mg/kg/d (2–4 times/d up to 1 g/d) |
Oral |
10 d |
|
Secondary Prevention |
|||
Benzathine (penicillin G) |
1.2 million U |
IM |
q3–4 wk |
or |
|||
Penicillin V |
250 mg |
Oral |
bid |
or |
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Sulfadiazine |
0.5 g (≤27 kg) |
Oral |
qd |
1.0 g (>27 kg) |
|||
|
Penicillin- and sulfadiazine-allergic patients |
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Erythromycin |
250 mg |
Oral |
bid |
bid, twice a day; IM, intramuscular; qd, every day.
A.Primary prevention. The most important step in the management of RF is the eradication of GAS infection, which prevents chronic and repetitive exposure of antigenic streptococcal components to the host immune system. However, no treatment can eradicate GAS completely in all patients because of high colonization rates.
1.Early therapy is advisable because it reduces both morbidity and the period of infectivity. Therapy started as late as 9 days after the onset of acute streptococcal pharyngitis is still effective in preventing primary attacks of RF.
2.Penicillin is the agent of choice primarily for its narrow spectrum of activity, long-standing proven efficacy, and low cost.
a.Best results are achieved with a single intramuscular (IM) dose of penicillin G benzathine. An IM regimen is preferred in patients unlikely to complete a 10-day course of oral therapy or in patients with personal or family history of RF or rheumatic heart disease. This preparation is painful; preparations that contain procaine penicillin are less painful.
b.In comparison with the IM regimen, the oral regimen has several disadvantages, such as lower compliance because of its longer duration, more complicated dosing schedules, drug interactions, and, more importantly, socioeconomic factors. The oral antibiotic of choice is penicillin V (phenoxymethylpenicillin) (see Table 20.3 for dosage information). A broader spectrum penicillin, such as amoxicillin, offers no microbiologic advantage over penicillin.
3.Patients allergic to penicillin:
a.Oral erythromycin can be used. The recommended dosage is erythromycin estolate or erythromycin ethyl succinate for 10 days. The maximum dose of erythromycin is 1 g/d.
c.Another alternative regimen for penicillin-allergic patients is a 10-day course with an oral cephalosporin. A first-generation cephalosporin with a narrower spectrum of action (cefazolin or cephalexin) is preferable to the broader spectrum antibiotics such as cefaclor, cefuroxime, cefixime, and cefpodoxime. Several reports support the evidence that a 10-day course with oral cephalosporin is superior to a 10-day course with oral penicillin and a 5-day course with selected oral cephalosporins is comparable to a 10-day course with oral penicillin for the eradication of GAS.
d.Sulfa-derived antibiotics (sulfonamides and trimethoprim) do not eradicate GAS in patients with pharyngitis, and tetracycline should be avoided because of the high prevalence of resistant strains.
B.Secondary prevention. Prophylaxis for preventing recurrences should start as soon as RF or rheumatic heart disease is diagnosed, as recurrences can sometimes be asymptomatic.
1.Penicillin in doses of 600,000 IU (patient’s weight < 27 kg) to 1.2 million IU (patient’s weight > 27 kg) every 4 weeks is the recommended regimen in most circumstances. The interval is reduced to 3 weeks for individuals at high risk for developing acute RF or living in endemic areas.
2.The duration of prophylaxis depends on the individual situation. Table 20.4 provides additional information.
TABLE 20.4 Duration of Therapy for Secondary Prevention of Rheumatic Fever |
|
Disease State |
Duration of Therapy |
RF + carditis + residual valvular disease |
At least 10 y postepisode and at least until the age of 25 y. Lifelong prophylaxis may be required (for more severe valvular disease) |
RF + carditis without valvular disease |
10 y or at least till 25 y, whichever is longer |
RF without carditis |
5 y or until the age of 18 y, whichever is longer |
RF after valve surgery |
Lifelong |
RF, rheumatic fever.
Data from Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806–1818.
a.Prophylaxis for recurrent RF in patients without cardiac manifestations should be continued for 5 years after the last RF attack or up to the age of 18 years, whichever is longer.
b.For patients with RF and carditis but no residual valvular disease, prophylaxis should extend for a period of 10 years or till age 25 whichever is longer.
c.Indefinite antibiotic prophylaxis is recommended in patients with severe valvular heart disease.
3.The success of oral prophylaxis depends on the patient’s understanding and adherence to the prescribed regimen. Oral agents are more appropriate for patients at lower risk for rheumatic recurrences. Some favor switching patients to oral prophylaxis when they have reached late adolescence or young adulthood and have remained free of rheumatic attacks for at least 5 years.
a.The preferred oral medication is penicillin V.
b.For patients with true or suspected allergy to penicillin, sulfadiazine can be used (Table 20.3). Erythromycin is an alternative.
c.It is important to keep in mind that even with optimal patient adherence, the risk of recurrence is higher with an oral than with an IM prophylactic regimen.
C.Endocarditis prophylaxis. Updated guidelines from the AHA published in 2007 recommend against routine prophylaxis for endocarditis in patients with rheumatic valvular disease undergoing dental or other procedures. Antibiotic prophylaxis is recommended only for patients with prosthetic valves, previous endocarditis, and certain forms of congenital heart disease and for heart transplant patients with vasculopathy (see Chapter 19).
D.Vaccines targeted against GAS. Several multivalent vaccines against GAS are currently in clinical trials. The M protein is the most promising target, but vaccine development has been complicated because there are multiple M-protein subtypes that are rheumatogenic. The use of a vaccine may prevent pharyngeal colonization, thereby removing population reservoirs, which allow for endemic disease.
VII.Screening
A.Screening in endemic areas. Given the significant burden of rheumatic heart disease, screening children and young adults has proven useful for those in endemic areas.
1.Screening generally involves three components: (1) eliciting a history of acute RF, (2) physical examination, and (3) echocardiography. Two screening approaches have been described in high-risk populations. First, physical examination including auscultation for murmur is followed by echocardiographic confirmation in those found to have a murmur. Alternatively, portable echocardiography is used for all followed by clinical examination of abnormal cases. Because auscultation has been shown to be clinician dependent and crude in detecting valve pathology, many cases of rheumatic heart disease go unidentified, favoring the echocardiographic approach to screening.
ACKNOWLEDGMENTS: The author thanks Drs. Stephen Gimple, Simone Nader, Mohammed Nasir Khan, and Chetan Vagesh Hampole for their contributions to earlier editions of this chapter.
Landmark Articles
Essop MR, Peters F. Contemporary issues in rheumatic fever and chronic rheumatic heart disease. Circulation. 2014;130:2181–2188.
Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131:1806–1818.
Woldu B, Bloomfield GS. Rheumatic heart disease in the twenty-first century. Curr Cardiol Rep. 2016;18:96.
Relevant Book Chapter
Mayosi MM. Rheumatic fever. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: WB Saunders; 2015:1837–1841.