Clinical manifestations and diagnosis of acute rheumatic fever
Authors
Allan Gibofsky, MD, JD, FACP, FCLM
John B Zabriskie, MD
Section Editor
Daniel J Sexton, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Sun Oct 03
00:00:00 GMT 2010 (More)
INTRODUCTION — Acute rheumatic fever (ARF) is a nonsuppurative sequela that occurs two to four weeks
following group A streptococcus pharyngitis and may consist of arthritis, carditis, chorea, erythema marginatum,
and subcutaneous nodules. Damage to cardiac valves may be chronic and progressive, resulting in cardiac
decompensation.
The clinical manifestations and diagnosis of ARF will be reviewed here. The epidemiology, pathogenesis, treatment
and prevention of this disorder are presented separately. (See "Epidemiology and pathogenesis of acute rheumatic
fever" and "Treatment and prevention of acute rheumatic fever".)
PREDISPOSING FACTORS — In developed countries, acute rheumatic fever is generally preceded by group A
streptococcal (GAS) tonsillopharyngitis, but not by GAS skin infection infections [1]. However, data from
developing areas where acute rheumatic fever and rheumatic heart disease are endemic suggest that this association
is less clear [2-4].
Among aboriginal communities of Australia, for example, the most common manifestation of group A streptococcal
infection is pyoderma; symptomatic group A streptococcal tonsillopharyngitis and/or pharyngeal colonization are
rare [2,3]. A possible explanation is that recurrent pyoderma due to group A streptococci may afford protection
against pharyngeal colonization and infection [3]. Alternatively, group G or group C streptococci with certain group
A streptococcal antigens or enzymes may be important for the pathogenesis of acute rheumatic fever [2]. Among
Australian aboriginals with ARF, group G and group C streptococci have been identified in the throat but not the
pyoderma lesions [2,3].
CLINICAL MANIFESTATIONS
Acute illness — Acute rheumatic fever occurs most frequently in children from 5 to 15 years of age; it is rare
among children in the first three years of life and among adults.
The diagnosis of ARF is established largely on clinical grounds. The initial description of clinical manifestations,
known as the Jones criteria, were first published by Jones in 1944 and revised in 1965 [5,6]. Subsequently, the
American Heart Association (AHA) established guidelines for the diagnosis of rheumatic fever in 1992, and the
Jones Criteria Working Group of the AHA reviewed this document in 2002 [1,7].
Acute rheumatic fever is characterized by group A streptococcal infection followed by clinical manifestations
outlined below [1].
The five major manifestations are:
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

Migratory arthritis (predominantly involving the large joints)
Carditis and valvulitis (eg, pancarditis)
Central nervous system involvement (eg, Sydenham chorea)
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
Erythema marginatum
Subcutaneous nodules
The four minor manifestations are:
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


Arthralgia
Fever
Elevated acute phase reactants [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)]
Prolonged PR interval
The probability of acute rheumatic fever is high in the setting of group A streptococcal infection followed by two
major manifestations or one major and two minor manifestations [1,7,8]. Two minor manifestations are not
diagnostic; follow up of such patients has not demonstrated delayed onset of acute rheumatic fever.
Monoarthritis may be observed in patients treated with antiinflammatory drugs. Therapy with glucocorticoids or
nonsteroidal antiinflammatory drugs before the signs and symptoms of acute rheumatic fever become distinct may
make it difficult to establish the diagnosis of acute rheumatic fever. In such cases, it is difficult to determine the
need for secondary rheumatic fever prophylaxis. There is no evidence that temporarily withholding such therapy has
any adverse effects.
There are three circumstances in which a presumptive diagnosis of acute rheumatic fever can be made without strict
adherence to the above criteria [1]:
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

Chorea as the only manifestation
Indolent carditis as the only manifestation in patients who come to medical attention months after acute
group A streptococcal infection.
Recurrent rheumatic fever in patients with a history of rheumatic fever or rheumatic heart disease. In the
absence of pericarditis or involvement of a new valve, it may be difficult establish a diagnosis of acute
carditis during an acute attack. Therefore, a presumptive diagnosis of recurrent acute rheumatic fever may
be made with one major or two minor criteria if there is evidence of a recent group A streptococcal
infection. Caution against using a single clinical finding (eg, monoarthritis, fever, arthralgia) as a criterion
for the diagnosis of recurrent disease has been suggested [7].
Strict adherence to the Jones criteria in areas of high prevalence may result in underdiagnosis. This was illustrated in
a report of 555 cases of confirmed acute rheumatic fever among Australian aboriginals in whom monoarthritis and
low-grade fever were important manifestations [9].
Arthritis — The natural history of arthritis due to rheumatic fever consists of inflammation affecting several joints
in quick succession, each lasting for a few days to a week [10]. The knees, ankles, elbows, and wrists are affected
most commonly; the leg joints are typically involved first. The onset of arthritis in different joints usually overlaps,
giving the appearance that the disease "migrates" from joint to joint. Thus, the terms "migrating" or "migratory" are
used to describe the polyarthritis of rheumatic fever. Onset and resolution of arthritis may be rapid (within 1 to 2
days) and the arthritis may be severe enough to severely limit movement. Joint involvement is more common and
more severe in teenagers and young adults than in children [11].
Arthritis usually is the earliest symptomatic manifestation of ARF, although asymptomatic carditis may develop
first. Joint pain usually is more prominent than objective signs of inflammation and is almost always transient.
Typically inflammation is present in multiple joints, and each joint is inflamed for no more than one week.
Radiography of an affected joint may demonstrate a slight effusion but is usually unremarkable.
The natural history of the polyarthritis in ARF is altered by empiric treatment with nonsteroidal antiinflammatory
drugs. In such cases arthritis subsides quickly in the joints affected and does not "migrate" to new joints. In one
series of patients with rheumatic fever who were treated for associated arthritis, involvement of a single large joint
was common [10]. In another series including 555 Aboriginal patients in Australia, monoarticular arthritis was also
described in 17 percent of cases [9].
Analysis of the synovial fluid in rheumatic fever with arthritis generally demonstrates sterile inflammatory fluid.
Carditis — Rheumatic fever causes a pancarditis, affecting the pericardium, epicardium, myocardium, and
endocardium. The presence of valvulitis is established by auscultatory findings together with echocardiographic
evidence of mitral or aortic regurgitation. However, echocardiography findings may be non-specific. Damage to
cardiac valves may be progressive and chronic, resulting in cardiac decompensation. Clinical manifestations and
diagnosis of carditis are discussed separately. (See "Natural history, screening, and management of rheumatic heart
disease", section on 'Acute rheumatic fever'.)
Sydenham chorea — Sydenham chorea (also known as chorea minor or "St. Vitus dance") is a neurologic disorder
consisting of abrupt, nonrhythmic involuntary movements, muscular weakness, and emotional disturbances [12].
Neurologic examination fails to reveal sensory losses or involvement of the pyramidal tract. (See "Sydenham
chorea".)
The movements frequently are more marked on one side, are occasionally unilateral (hemichorea), and cease during
sleep. Muscle weakness is best demonstrated by asking the patient to squeeze the examiner's hands. The pressure of
the patient's grip increases and decreases capriciously, a phenomenon known as relapsing grip or "milk maids sign."
Diffuse hypotonia may be present. Emotional changes manifest with outbursts of inappropriate behavior including
crying and restlessness. In rare cases, psychologic manifestations are severe and may result in transient psychosis.
Chorea may have present up to eight months after streptococcal infections; this is a longer latent period than other
rheumatic manifestations [13]. Some patients with chorea have no other clinical symptoms but should undergo
evaluation for carditis with echocardiogram.
Erythema marginatum — Erythema marginatum is an evanescent, pink or faintly red, non-pruritic rash involving
the trunk and sometimes the limbs but not the face [14]. The lesion extends centrifugally with return of the skin in
the center to a normal appearance. The outer edge of the lesion is sharp; the inner edge is diffuse. The lesion is also
known as "erythema annulare" since the margin of the lesion is usually continuous, making a ring (picture
1 and picture 2).
Individual lesions may appear, disappear, and reappear in a matter of hours. A hot bath or shower may make them
more evident. Erythema marginatum usually occurs early in the course of ARF in patients with acute carditis, but
may persist or recur when all other manifestations of disease have disappeared [15]. Cases have been reported in
patients with chronic carditis [10]. In some cases the lesions are first noticed late in the course of the illness or even
during convalescence.
Subcutaneous nodules — Subcutaneous nodules in ARF are firm, painless lesions ranging from a few millimeters
to 2 cm in size. The nodules are usually located over a bony surface or prominence or near tendons (usually extensor
surfaces) and are usually symmetric. The overlying skin is not inflamed and usually can be moved over the nodules
(picture 3) [16]. The number of nodules varies from a single lesion to a few dozen; the average number is three or
four.
Rheumatic subcutaneous nodules generally appear after the first weeks of illness, usually in patients with relatively
severe carditis. Typically nodules are present for one or more weeks; they rarely persist for more than a month.
Nodules of ARF are smaller and more short-lived than the nodules of rheumatoid arthritis. The elbows are involved
most frequently in both rheumatic fever and rheumatoid arthritis; they may be distinguished in that rheumatic fever
nodules occur most commonly on the olecranon, while rheumatoid nodules usually are found 3 to 4 cm distally.
In contemporary outbreaks of ARF, nodules have been the least common manifestation (less than 5 percent of
patients) [17].
Late sequelae — Rheumatic heart disease is the most severe sequela of acute rheumatic fever. It usually occurs 10
to 20 years after the original illness and is the most common cause of acquired valvular disease in the world [18,19].
The mitral valve is more commonly involved than the aortic valve. Mitral stenosis, caused by severe calcification of
the mitral valve, is the classic finding in rheumatic heart disease.
The incidence of rheumatic heart disease in patients with a history of ARF is variable; in general, valvular damage
manifesting as a murmur later in life is likely to occur in about 50 percent of patients with evidence of carditis at
initial presentation [20,21].
DIAGNOSIS — Acute rheumatic fever is characterized by group A streptococcal infection followed by the clinical
manifestations outlined above. Laboratory studies can be used to establish the diagnosis of GAS infection, evaluate
acute phase reactants, and evaluate cardiac function. The utility of the various criteria for ARF likely varies as a
function of disease incidence. (See 'Clinical manifestations' above and 'Carditis' above.)
Streptococcal pharyngitis may be diagnosed in one of the following ways:



Positive throat culture for group A beta-hemolytic streptococci
Positive rapid streptococcal antigen test
Elevated or rising antistreptolysin O antibody titer
Throat cultures are negative in about 75 percent of patients by the time manifestations of rheumatic fever appear [1].
(See "Evaluation of acute pharyngitis in adults".)
Anti-streptolysin O (ASO) titers vary with age, season, and geography [22]. Healthy children of elementary school
age commonly have titers of 200 to 300 Todd units per mL; asymptomatic pharyngeal strep carriers tend to have
very low titers, just above detectable. Following streptococcal pharyngitis, the antibody response peaks at about four
to five weeks, which usually is during the second or third week of rheumatic fever. Antibody titers fall off rapidly in
the next several months and after six months have a slower decline. For these reasons, it may be useful to collect one
specimen when the diagnosis of ARF is first suspected and another two weeks later.
About 80 percent of patients with documented ARF demonstrate a rise in antistreptolysin titer, although this cannot
be used as a measure of rheumatic activity. A negative antistreptolysin titer should prompt testing for other
antistreptococcal antibodies such as anti-DNAse B (detectable for six to nine months following infection),
streptokinase, and antihyaluronidase; commercial tests for these antibodies are available. About 90 percent of
patients with documented ARF have positive findings if two antigens are evaluated; about 95 percent have positive
findings if three antigens are evaluated.
Acute-phase reactants are increased in ARF. Both serum C-reactive protein (CRP) and the erythrocyte sedimentation
rate (ESR) are invariably elevated during the active rheumatic process unless they are suppressed by antirheumatic
drugs [23]. CRP or ESR are useful for monitoring "rebounds" of inflammation as treatment is tapered. A normal
result obtained a few weeks after discontinuing antirheumatic therapy suggests that the course of the illness is
complete (unless chorea appears). The CRP is probably more useful since it typically normalizes over a matter of
days once an episode of acute inflammation has resolved, while the ESR may stay elevated for up to two months
after a transient inflammatory stimulus.
A mild normochromic normocytic anemia of chronic inflammation may be observed during acute rheumatic fever.
Suppressing the inflammation usually improves the anemia; iron therapy generally is not indicated.
Complement levels are usually normal in ARF. In contrast, hypocomplementemia is typically observed in the setting
of poststreptococcal glomerulonephritis.
Analysis of the synovial fluid in rheumatic fever with arthritis generally demonstrates sterile inflammatory fluid.
(See 'Arthritis' above.)
Issues related to electrocardiogram and echocardiogram findings are discussed above (see 'Carditis' above).
DIFFERENTIAL DIAGNOSIS — The approach to polyarticular joint pain in children and adults is discussed
separately. (See "Evaluation of the child with joint pain or swelling" and "Evaluation of the adult with polyarticular
pain".)
Poststreptococcal reactive arthritis — Several investigators have speculated that some cases of arthritis occurring
after a streptococcal infection may not be caused by ARF. This disorder has been called poststreptococcal reactive
arthritis (PSRA) [24-29]. Issues related to reactive arthritis in general are discussed separately. (See "Reactive
arthritis (formerly Reiter syndrome)", section on 'Acute rheumatic fever'.)
The following observations have been used to support the notion that PSRA is a separate disorder [30,31]:


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
The latent period between the antecedent streptococcal infection and the onset of migratory arthritis is
shorter (one to two weeks) than the two to three weeks usually seen in classic ARF.
The response of the arthritis to aspirin and other nonsteroidal medications is poor in comparison to the
dramatic response seen in classical ARF.
Evidence of carditis is not seen in these patients, and the severity of the arthritis is quite marked.
Extraarticular manifestations such as tenosynovitis and renal abnormalities often are seen in these patients.
Acute phase reactants (ESR, CRP) tend to be lower than in the setting of ARF.
However, these patients may actually have ARF, with the above observations being explained by other factors. As
an example, variations in the response to Aspirin in affected children may be caused by inadequate salicylate levels.
Furthermore, an unusual clinical course should not be sufficient to exclude the diagnosis of ARF. Migratory arthritis
without evidence of other major Jones criteria, if supported by two minor manifestations, still must be considered
acute rheumatic fever, especially in children.
Clearly defining this reactive arthritis as a rheumatic fever variant has important implications for secondary
prophylactic treatment. Some investigators feel that PSRA is a benign condition without need for prophylaxis [26].
On the other hand, both the 1992 guidelines and the 2002 update reached the following conclusions [6,22]:


Although the relationship between PSRA and acute rheumatic fever remains unresolved, patients who
fulfill the Jones criteria should be considered to have acute rheumatic fever.
Among patients who do not fulfill the Jones criteria, the diagnosis of PSRA should be made only after
excluding other rheumatic diseases such as Lyme disease and rheumatoid arthritis.
In our experience, these patients usually fulfill the Jones criteria (one major, two minor). Thus, they should be
treated as if they have acute rheumatic fever, and appropriate antibiotic prophylaxis should be prescribed [32,33].
This view is supported by a study in which 50 percent of children with signs of migratory arthritis alone went on to
develop significant valvular damage after a long follow-up period [34]. These children presented with their
streptococcal illness between 1939 and 1955, before penicillin therapy was widely available. (See "Treatment and
prevention of acute rheumatic fever", section on 'Poststreptococcal reactive arthritis'.)
Another series included 12 children who were diagnosed with PSRA between 1978 and 1985 and were treated with
10 days of penicillin, but no prophylaxis [35]. One child developed classic acute rheumatic fever with valvulitis 18
months after the initial episode. This proportion is similar to the approximately 10 percent of patients who develop
recurrent ARF with valvulitis after an initial episode of ARF that did not include carditis.
SUMMARY

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
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

Acute rheumatic fever (ARF) is a nonsuppurative sequela of group A streptococcus pharyngitis that occurs
two to four weeks following infection. The diagnosis of ARF is established largely on clinical grounds. The
probability of acute rheumatic fever is high in the setting of group A streptococcal infection followed by
two major manifestations or one major and two minor manifestations. (See 'Clinical manifestations' above.)
The five major manifestations are migratory arthritis (predominantly involving the large joints), carditis
and valvulitis (eg, pancarditis), central nervous system involvement (eg, Sydenham chorea), erythema
marginatum, and subcutaneous nodules. The four minor manifestations are arthralgia, fever, elevated acute
phase reactants, and prolonged PR interval. (See 'Acute illness' above.)
Arthritis usually is the earliest symptomatic manifestation of ARF. The natural history consists of
inflammation affecting several joints in quick succession with overlapping onset, giving the appearance
that the disease "migrates" from joint to joint. Joint pain usually is more prominent than objective signs of
inflammation and is almost always transient. (See 'Arthritis' above.)
Rheumatic fever causes a pancarditis, affecting the pericardium, epicardium, myocardium, and
endocardium. (See 'Carditis' above.)
Sydenham chorea (also known as chorea minor or "St. Vitus dance") is a neurologic disorder consisting of
abrupt, nonrhythmic involuntary movements, muscular weakness, and emotional disturbances.
(See 'Sydenham chorea' above.)
Erythema marginatum is an evanescent, pink or faintly red, non-pruritic rash involving the trunk and
sometimes the limbs but not the face (picture 1 andpicture 2). The lesion extends centrifugally with return
of the skin in the center to a normal appearance. (See 'Erythema marginatum' above.)
Subcutaneous nodules are firm, painless lesions ranging from a few millimeters to 2 cm in size (picture 3).
The nodules are usually located over a bony surface or prominence or near tendons (usually extensor
surfaces) and are usually symmetric. (See 'Subcutaneous nodules' above.)
Investigators have speculated that some cases of arthritis occurring after a streptococcal infection may not
be caused by ARF. Evidence of carditis is not seen in these patients. This disorder has been called
poststreptococcal reactive arthritis. (See 'Poststreptococcal reactive arthritis' above.)
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McDonald MI, Towers RJ, Andrews RM, et al. Low rates of streptococcal pharyngitis and high rates of pyoderma in
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Noel TP, Zabriskie J, Macpherson CN, Perrotte G. Beta-haemolytic streptococci in school children 5-15 years of age
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Ferrieri P, Jones Criteria Working Group. Proceedings of the Jones Criteria workshop. Circulation 2002; 106:2521.
Rheumatic fever and rheumatic heart disease: report of a WHO Expert Consulatation. 2001: Geneva, Switzerland.
Carapetis JR, Currie BJ. Rheumatic fever in a high incidence population: the importance of monoarthritis and low
grade fever. Arch Dis Child 2001; 85:223.
FEINSTEIN AR, SPAGNUOLO M. The clinical patterns of acute rheumatic fever: a reapraisal. Medicine
(Baltimore) 1962; 41:279.
Wallace, MR, Garst, PD, Papadimos, TJ, Oldfield, EC. The return of acute rheumatic fever in young adults. JAMA
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SACKS L, FEINSTEIN AR, TARANTA A. A controlled psychologic study of Sydenham's chorea. J Pediatr 1962;
61:714.
Eshel G, Lahat E, Azizi E, et al. Chorea as a manifestation of rheumatic fever--a 30-year survey (1960-1990). Eur J
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BURKE JB. Erythema marginatum. Arch Dis Child 1955; 30:359.
Perry CB. Erythema marginatum (rheumaticum). Arch Dis Child 1937; 12:233.
BALDWIN JS, KERR JM, KUTTNER AG, DOYLE EF. Observations on rheumatic nodules over a 30-year period.
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Ayoub EM. Resurgence of rheumatic fever in the United States. The changing picture of a preventable illness.
Postgrad Med 1992; 92:133.
Marcus RH, Sareli P, Pocock WA, Barlow JB. The spectrum of severe rheumatic mitral valve disease in a
developing country. Correlations among clinical presentation, surgical pathologic findings, and hemodynamic
sequelae. Ann Intern Med 1994; 120:177.
Horstkotte D, Niehues R, Strauer BE. Pathomorphological aspects, aetiology and natural history of acquired mitral
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Albert DA, Harel L, Karrison T. The treatment of rheumatic carditis: a review and meta-analysis. Medicine
(Baltimore) 1995; 74:1.
Meira ZM, Goulart EM, Colosimo EA, Mota CC. Long term follow up of rheumatic fever and predictors of severe
rheumatic valvar disease in Brazilian children and adolescents. Heart 2005; 91:1019.
RANTZ LA, RANDALL E, RANTZ HH. Antistreptolysin O; a study of this antibody in health and in hemolytic
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Schaffer FM, Agarwal R, Helm J, et al. Poststreptococcal reactive arthritis and silent carditis: a case report and
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Arnold MH, Tyndall A. Poststreptococcal reactive arthritis. Ann Rheum Dis 1989; 48:686.
Aviles RJ, Ramakrishna G, Mohr DN, Michet CJ Jr. Poststreptococcal reactive arthritis in adults: a case series.
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description, revealing its distinction from acute rheumatic fever. J Intern Med 1999; 245:261.
Mackie SL, Keat A. Poststreptococcal reactive arthritis: what is it and how do we know? Rheumatology (Oxford)
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poststreptococcal reactive arthritis. Arthritis Rheum 2009; 60:987.
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Moon RY, Greene MG, Rehe GT, Katona IM. Poststreptococcal reactive arthritis in children: a potential predecessor
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Infect Dis J 1988; 7:683
Figure 1
Figure 2
Figure 3
Epidemiology and pathogenesis of acute rheumatic fever
Authors
Allan Gibofsky, MD, JD, FACP, FCLM
John B Zabriskie, MD
Section Editors
Daniel J Sexton, MD
Sheldon L Kaplan, MD
Robert Sundel, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu Mar 12
00:00:00 GMT 2009 (More)
INTRODUCTION — Acute rheumatic fever (ARF) is a delayed, nonsuppurative sequela of a pharyngeal infection
with the group A streptococcus (GAS). Following the initial pharyngitis, a latent period of two to three weeks occurs
before the first signs or symptoms of ARF appear [1]. The disease presents with various manifestations that may
include arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum.
The epidemiology and pathogenesis of ARF will be reviewed here. The clinical manifestations, diagnosis, treatment,
and prevention of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of acute
rheumatic fever" and "Treatment and prevention of acute rheumatic fever".)
EPIDEMIOLOGY — In developing areas of the world, acute rheumatic fever and rheumatic heart disease are
estimated to affect nearly 20 million people and are the leading causes of cardiovascular death during the first 5
decades of life [2]. Worldwide, there are 470,000 new cases of rheumatic fever and 233,000 deaths attributable to
rheumatic fever or rheumatic heart disease each year; most occur in developing countries and among indigenous
groups [2,3]. The mean incidence of ARF is 19 per 100,000 [4].
In the United States and other developed countries, the incidence of ARF is much lower at 2 to 14 cases per
100,000; this is probably due to improved hygienic standards and routine use of antibiotics for acute pharyngitis
[5,6]. Many cases that do occur are part of localized outbreaks [7-12]. (See"Evaluation of acute pharyngitis in
adults" and "Approach to diagnosis of acute infectious pharyngitis in children and adolescents".)
During epidemics in the mid 1900s, as many as 3 percent of untreated acute streptococcal sore throats were followed
by rheumatic fever; in endemic infections, the incidence of rheumatic fever is substantially less [13].
Rheumatogenic strains — The observation in some studies that only a few M serotypes (types 3, 5, 6, 14, 18, 19,
24, and 29) were implicated in outbreaks of rheumatic fever in the United States suggested a particular
"rheumatogenic" potential of certain strains of GAS [7,14-16].
To address the "rheumatogenic" potential of GAS, a serologic surveillance study compared the M types of GAS
recovered from children in Chicago with acute pharyngitis during the time period 1961 to 1968 to the GAS strains
recovered from Chicago children and children from across the United States in the time period 2000 to 2004 [15].
Rheumatogenic strains (eg, types 3, 5, 6, 14, 18, 19, and 29) were less prevalent among the latter isolates (10.6
versus 49.7 percent in the earlier time period) [15].
The authors hypothesized that the marked decrease in the incidence of acute rheumatic fever in the United States
correlates with the replacement of rheumatogenic types by nonrheumatogenic types. However, an accompanying
editorial noted that although the prevalence of rheumatogenic strains decreased two- to fivefold, the reduction in the
incidence of ARF over the same period was ≥20-fold [17]. Thus, a shift in the prevalence of rheumatogenic M type
GAS strains is not solely responsible for the decrease in ARF.
Our own series, gathered over a 20-year period, has produced different results. We isolated a large number of
different M serotypes, including six strains that were nontypable. In addition, several different M types were isolated
from the patients seen during a mid-1980s outbreak of ARF in Utah; these strains were both mucoid and nonmucoid in character [18]. In addition, M serotypes different from those in the United States have been associated
with ARF in Trinidad and Hawaii [19-21].
Thus, the issue of potential "rheumatogenic" strains remains unresolved. A streptococcal strain capable of causing a
well-documented pharyngitis almost always is potentially capable of causing rheumatic fever, although some
exceptions have been recorded [22]. The lack of specific rheumatogenic strains also can explain the relatively high
risk of recurrent disease with new streptococcal infections, in contrast to poststreptococcal glomerulonephritis, in
which only a few "nephritogenic" strains appear to be capable of inducing the disease (eg, type 12 with pharyngitis
and type 49 with impetigo), and recurrent disease is uncommon [23,24].
PATHOGENESIS — The pathogenic mechanisms that lead to the development of acute rheumatic fever remain
incompletely understood. Clearly streptococcal pharyngeal infection is required, and genetic susceptibility may be
present. On the other hand, evidence is sparse that toxins produced by the streptococcus are important.
Within this framework, molecular mimicry is thought to play an important role in the initiation of the tissue injury
(see 'Molecular mimicry' below). However, the factors responsible for maintenance of the process remain unclear.
Role of the streptococcus — Despite the lack of evidence for the direct involvement of GAS in the affected tissues
of patients with ARF, significant epidemiologic and immunologic evidence indirectly implicates the GAS in the
initiation of disease.




Outbreaks of rheumatic fever closely follow epidemics of streptococcal pharyngitis or scarlet fever with
associated pharyngitis [22,25].
Adequate treatment of a documented streptococcal pharyngitis markedly reduces the incidence of
subsequent rheumatic fever [26].
Appropriate antimicrobial prophylaxis prevents the recurrence of disease in patients who have had ARF
[14,27].
Most patients with ARF have elevated antibody titers to at least one of (if not all) three antistreptococcal
antibodies (streptolysin "O", hyaluronidase, and streptokinase), whether or not they recall an antecedent
sore throat [28].
In contrast to the high sensitivity of antistreptococcal antibodies for the documentation of streptococcal infection,
the rate of isolation of GAS from the oropharynx of patients with ARF is extremely low, even in populations that
generally do not have access to microbial antibiotics. The clinical documentation of an antecedent pharyngitis also
appears to have an age-related discrepancy. One study, for example, noted that the recollection of pharyngitis
approached 70 percent in older children and young adults versus only 20 percent in younger children [8]. Thus, a
high index of suspicion of ARF is important, particularly in children or young adults presenting with signs of
arthritis and/or carditis, even in the absence of a documented episode of pharyngitis.
In certain areas, it has been suggested that ARF might be due to non-group A streptococcal strains (eg, group C and
group G) that inherited certain group A streptococcal antigens or enzymes that are important for initiating ARF [29].
(See "Clinical manifestations and diagnosis of acute rheumatic fever", section on 'Predisposing factors'.)
Importance of pharyngitis — Streptococcal pharyngitis is the only streptococcal infection that has been associated
with ARF. As an example, there have been many documented outbreaks of impetigo that can cause
glomerulonephritis but almost never ARF [24,30]. In addition, a study of patients in Trinidad, where both impetigo
and rheumatic fever can be concomitant infections, found that the strains colonizing the skin were different from
those associated with rheumatic fever and that the presence of impetigo did not influence the incidence of ARF [30].
In communities of aboriginal Australians, pharyngeal carriage of GAS is uncommon although rates of ARF are high
[29]. Such findings have led to the hypothesis that ARF may arise from GAS pyoderma or from pharyngitis due to
non-group A streptococcal strains that inherited certain group A streptococcal antigens or enzymes that are
important for initiating ARF [29]. These issues are discussed separately. (See "Clinical manifestations and diagnosis
of acute rheumatic fever", section on 'Predisposing factors'.)
Bacterial genetic factors may be an important determinant of the site of GAS infection. Five chromosome patterns of
emm genes, which code for M and M-like surface proteins, have been recognized and labeled A-E. Pharyngeal
strains typically have patterns A-C, whereas almost all impetigo strains show D and E patterns [31].
(See 'Rheumatogenic strains' above.)
Another factor affecting localization to the pharynx may be CD44, a hyaluronic acid binding protein that appears to
act as a pharyngeal receptor for GAS. After intranasal inoculation, GAS colonize the oropharynx in wild-type mice
but not transgenic mice that do not express CD44 [32].
A few theories have tried to explain why ARF is only associated with streptococcal pharyngitis, but the exact
explanation remains obscure. GAS fall into two main classes based upon differences in the C repeat regions of the
M protein [33]. One class is associated with streptococcal pharyngeal infection; the other (with some exceptions)
belongs to strains commonly associated with impetigo. Thus, the particular strain of streptococcus may be crucial in
initiating the disease process. The pharyngeal site of infection, with its large repository of lymphoid tissue, also may
be important in the initiation of the abnormal humoral response by the host to those antigens crossreactive with
target organs.
Impetigo strains do colonize the pharynx. However, they do not appear to elicit as strong an immunologic response
to the M protein moiety as the pharyngeal strains [34,35]. This observation may prove to be an important factor,
especially in light of the known cross-reaction between various streptococcal structures and mammalian proteins.
Molecular mimicry — As a result of molecular mimicry, antibodies directed against GAS antigens crossreact with
host antigens [36-40]. In addition to the role of antibody, observations suggest a role for cellular immunity in
molecular mimicry in ARF. A study of human heart-intralesional T cell clones found that 63 percent of patients
reacted with meromyosin [41]. Furthermore many of these clones cross-reacted with myosin, valve-derived proteins,
as well as streptococcal M5 peptides.
Carditis — Streptococcal M protein and N-acetyl-beta-D-glucosamine (NABG, the immunodominant carbohydrate
antigen of GAS) share epitopes with myosin [37,38,40]. Rodents immunized with recombinant streptococcal M
protein type 6 develop both valvulitis and focal cardiac myositis [42].
The potential clinical significance of these observations was illustrated in a study in which monoclonal antibodies
were generated from tonsillar or peripheral blood lymphocytes of patients infected with GAS [39]. Some of these
antibodies crossreacted with myosin and certain other proteins. In addition, antimyosin antibodies purified from
patients with acute rheumatic fever crossreacted with GAS and M protein. Similar antibodies were present in much
lower concentrations in some normal subjects.
In a later report, a monoclonal antibody isolated from a patient with rheumatic carditis was directed against myosin
and NABG [40]. The antibody was cytotoxic for human endothelial cell lines and reacted with human valvular
endothelium; this reactivity was inhibited by myosin>laminin>NABG. The reactivity with the extracellular matrix
protein laminin may explain the reactivity against the valve surface.
Chorea — Molecular mimicry may also be involved in the development of Sydenham chorea. In an animal model,
monoclonal antibodies that caused chorea bound to both NABG and mammalian lysoganglioside [43]. Exposure of
cultured human neuronal cells to either monoclonal antibodies or serum from patients with chorea led to induction
of calcium/calmodulin protein kinase. Exposure to serum from patients following streptococcal infection that was
not complicated by chorea did not have this effect on neuronal cells. (See "Sydenham chorea".)
Genetic susceptibility — The concept that rheumatic fever might be the result of a host genetic predisposition has
intrigued investigators for more than 100 years [44]. During that time, suggestions have included the theory that the
disease is transmitted in an autosomal dominant fashion [45], in an autosomal recessive fashion with limited
penetrance [46], or via genes related to determinants of blood group secretor status [47].
Renewed interest in the genetics of rheumatic fever occurred with the recognition that gene products of the human
MHC were associated with certain clinical diseases. Several studies have reported genetic associations with ARF;
some appear to be MHC-related, others are non-MHC-related.



Using an alloserum from a multiparous donor, an increased frequency of a B cell alloantigen that was not
MHC-related was reported in several genetically distinct and ethnically diverse populations of individuals
with ARF [48].
In another report, monoclonal antibodies were generated by immunizing mice with B cells from patients
with rheumatic fever. One of these antibodies, D8/17, was found to identify a marker expressed on
increased numbers (>20 percent) of B cells in 100 percent of patients with ARF of diverse ethnic origins
[49]. The percentage of D8/17+ B cells ranged from 4 to 6 percent in approximately 90 to 95 percent of
nonaffected normal subjects. In contrast, the number of D8/17+ B cells was one standard deviation above
normal (10 to 12 percent) in 4 to 7 percent of subjects. Thus, this marker might identify a population of
rheumatic fever-susceptible individuals. The antigen defined by this monoclonal antibody showed no
association with or linkage to any known MHC allele, nor did it appear to be related to B cell activation
antigens.
An increased frequency of the classic MHC class II alleles, HLA-DR4 and DR2, has been noted in
Caucasian and black patients with rheumatic heart disease [50]. Other studies have implicated DR1 and
DRW6 as susceptibility factors in South African black patients with rheumatic heart disease [51] and a
close association with HLA-DR7 and DW53 has been noted in RF patients in Brazil [52].
These apparently differing results concerning HLA antigens and RF susceptibility have led to speculation that the
reported associations might be of genes close to, but not identical to, the RF susceptibility gene. Alternatively, and
more likely, susceptibility to ARF is polygenic, and the D8/17 antigen might be associated with only one of the
genes conferring susceptibility; whereas another might be the MHC complex encoding for DR antigens. Although
the exact explanation remains to be determined, the presence of an increased percentage of D8/17+ B cells appears
to identify a population at special risk of contracting ARF.
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Treatment and prevention of acute rheumatic fever
Authors
Allan Gibofsky, MD, JD, FACP, FCLM
John B Zabriskie, MD
Section Editor
Daniel J Sexton, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Tue Aug 16
00:00:00 GMT 2011 (More)
INTRODUCTION — Acute rheumatic fever (ARF) is a nonsuppurative complication of pharyngeal infection with
group A streptococcus. Signs and symptoms of ARF develop two to three weeks following pharyngitis and include
arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum [1]. (See"Clinical manifestations and
diagnosis of acute rheumatic fever".)
In developing areas of the world, acute rheumatic fever and rheumatic heart disease are estimated to affect nearly 20
million people and are the leading causes of cardiovascular death during the first five decades of life [2]. In the
United States and other developed countries, the incidence of ARF is much lower, likely due to improved hygienic
standards and routine use of antibiotics for acute pharyngitis [3]. (See "Epidemiology and pathogenesis of acute
rheumatic fever".)
There is no therapy that slows progression of valvular damage in the setting of ARF. There are three major goals of
treatment:



Symptomatic relief of acute disease manifestations
Eradication of the group A beta-hemolytic streptococcus (GAS)
Prophylaxis against future GAS infection to prevent recurrent cardiac disease
Issues related to treatment and secondary prevention of rheumatic fever will be reviewed here. Issues related to
primary prevention (eg, treatment of streptococcal tonsillopharyngitis) and the epidemiology, pathogenesis, clinical
manifestations and diagnosis of acute rheumatic fever are discussed in detail separately. (See "Treatment and
prevention of streptococcal tonsillopharyngitis" and "Epidemiology and pathogenesis of acute rheumatic
fever" and "Clinical manifestations and diagnosis of acute rheumatic fever".)
TREATMENT — Treatment of acute rheumatic fever consists of antibiotic therapy, heart failure management, and
anti-inflammatory therapy.
Antibiotic therapy — Patients with acute rheumatic fever should be initiated on antibiotic therapy to eradicate GAS
carriage. Treatment should proceed as delineated for management of streptococcal pharyngitis, whether or not
pharyngitis is present at the time of diagnosis (table 1) [4]. In addition, household contacts should have throat
cultures performed; those with positive results should also receive a full course of antibiotic therapy, even if
asymptomatic. (See"Treatment and prevention of streptococcal tonsillopharyngitis".)
Carditis — Patients with severe carditis (significant cardiomegaly, congestive heart failure, and/or third-degree
heart block) should be treated with conventional therapy for heart failure. (See "Clinical manifestations and
diagnosis of acute rheumatic fever" and "Overview of the therapy of heart failure due to systolic dysfunction".)
Valve surgery may be necessary when heart failure due to regurgitant lesions cannot be managed with medical
therapy alone [5-7]. Surgical outcomes are generally better if valve surgery can be performed when carditis is
quiescent [6]. Valve repair, if feasible, is preferred over valve replacement since repair avoids the need for long-term
anticoagulation associated with mechanical valves and the long-term risk of deterioration of a bioprosthesis [5,7].
Aspirin (80 to 100 mg/kg per day in children and 4 to 8 g/day in adults) is the major anti-inflammatory agent for
relief of symptoms due to acute rheumatic fever [8]. The efficacy of other anti-inflammatory drugs in the setting of
active rheumatic carditis is uncertain [9-13]. A meta-analysis of eight randomized trials including 996 patients with
acute rheumatic fever found no significant difference in the risk of cardiac disease at one year between the
corticosteroid-treated and aspirin-treated groups [13]. No reduction in the risk of heart valve lesions was observed
with corticosteroids or intravenous immunoglobulin [13].
Arthritis and rash — Anti-inflammatory agents are the mainstay of symptomatic management due to acute
rheumatic fever [8]. Aspirin (80 to 100 mg/kg per day in children and 4 to 8 g/day in adults) is helpful for reducing
discomfort related to arthritis and fever. Anti-inflammatory therapy should be continued until all symptoms have
resolved. Normalization of inflammatory markers (erythrocyte sedimentation rate and C-reactive protein
concentration) may be used as indicator of resolution. The rash associated with ARF is temporary and does not
require specific treatment, although antihistamines may help to alleviate pruritus. (See "Aspirin: Mechanism of
action, major toxicities, and use in rheumatic diseases".)
PREVENTION — Prevention of initial and recurrent attacks of rheumatic fever depends on control of group A
streptococcal tonsillopharyngitis [14,15].
Primary prevention — Prevention of initial attack of rheumatic fever (primary prevention) is accomplished by
prompt diagnosis and antibiotic treatment of group A streptococcal tonsillopharyngitis. These issues are discussed in
detail separately. (See "Evaluation of acute pharyngitis in adults" and "Approach to diagnosis of acute infectious
pharyngitis in children and adolescents" and "Treatment and prevention of streptococcal tonsillopharyngitis".)
Appropriate antibiotic treatment of streptococcal pharyngitis prevents acute rheumatic fever in most cases [16].
However, at least one third of acute rheumatic fever episodes occur in the setting of inapparent streptococcal
infection [17]. In addition, rheumatic fever is not preventable in symptomatic patients who do not seek medical care.
Streptococcal skin infections (such as impetigo or pyoderma) have not been proven to lead to acute rheumatic fever.
(See "Impetigo".)
Secondary prevention — Patients who have had an attack of rheumatic fever and develop subsequent GAS
pharyngitis are at high risk for a recurrent attack of rheumatic fever, with progression in severity of rheumatic heart
disease from the initial episode. The most effective method to limit progression of rheumatic heart disease severity
is prevention of recurrent GAS pharyngitis, especially since GAS infection need not be symptomatic to trigger a
recurrent attack of rheumatic fever.
For these reasons, prevention of recurrent rheumatic fever (secondary prevention) requires continuous antimicrobial
prophylaxis, rather than recognition and treatment of acute GAS pharyngitis episodes. Continuous prophylaxis is
warranted for patients with well-documented history of rheumatic fever (including cases with Syndenham chorea as
the sole manifestation) and those with definite evidence of rheumatic heart disease. (See "Clinical manifestations
and diagnosis of acute rheumatic fever".)
Prior to initiation of prophylaxis, a full therapeutic course of antibiotic therapy should be given to patients with acute
rheumatic fever to eradicate residual GAS, even if a throat culture is negative (table 1). (See 'Primary
prevention' above.)
Prophylactic antibiotics should be initiated immediately at the end of the therapeutic antibiotic course. During the
course of prophylaxis, patients and their household contacts who develop acute episodes of group A streptococcal
pharyngitis should be evaluated and treated promptly as outlined separately. (See"Treatment and prevention of
streptococcal tonsillopharyngitis".)
Duration — Secondary prevention for prevention of recurrent rheumatic fever consists of years of prophylactic
antibiotic administration. The total duration depends risk of recurrent rheumatic fever and severity of disease.
The risk of recurrent rheumatic fever depends on several factors [4,10]:





The number of previous attacks
Time since the last attack
Risk of exposure to streptococcal infections
Patient age
Presence or absence of cardiac involvement
Risk is increased among individuals with ongoing exposure to streptococcal infections including children, those in
close contact with children (parents, healthcare workers) and those living in crowded situations (college students,
military personnel) [18]. Risk increases with number of previous attacks but decreases as the interval lengthens since
the most recent attack.
The optimal duration of antibiotic prophylaxis following acute rheumatic fever is uncertain. Patients who have had
rheumatic carditis (with or without valvular disease) are at relatively high risk for recurrent carditis and are likely to
sustain increasingly severe cardiac involvement with each recurrence [19,20]. Therefore, in general, prophylaxis in
the setting of carditis should continue until the patient is a young adult (21 years of age), which is usually 10 years
from an acute attack with no recurrence (table 2) [4,21,22].
This approach was evaluated in a Chilean study of 59 patients with history of ARF judged to be at relatively low risk
for recurrence of acute rheumatic fever [22]. Among patients with history of ARF without carditis, prophylaxis was
discontinued after 5 years or at age 18 (whichever was longer). During 3349 patient-months of followup, only two
acute rheumatic fever recurrences were observed (0.7 per 100 patient-years). These data suggest that acute
rheumatic fever prophylaxis can likely be discontinued safely in young adults judged to be at low risk for recurrence
who are maintained under careful prospective surveillance.
The duration of prophylaxis following acute rheumatic fever is outlined by severity category in the Table (table
2) [4,23]. Antibiotic prophylaxis should continue even after valve surgery, including prosthetic valve replacement.
Upon reaching the end of a planned course for secondary prophylaxis, the risk for GAS exposure and severity of
valvular disease should be reviewed. A decision regarding cessation or continuation of antibiotic prophylaxis should
be made based on individual clinical risks and benefits.
Antibiotic selection — The preferred antibiotic approach for secondary prevention of recurrent rheumatic fever is
administration of long acting benzathinepenicillin G (Bicillin L-A) intramuscularly every 4 weeks (table 3) [4,24].
In populations where the incidence of rheumatic fever is particularly high, administration every 2 to 3 weeks is
appropriate. In the United States this is warranted only for those who have had recurrent acute rheumatic fever
despite adherence to a regimen administered every 4 weeks.
The long term benefits of intramuscular benzathine penicillin G prophylaxis outweigh the risk of allergic reaction, as
life threatening allergic reactions are rare [25]. However, the advantages of this approach must be weighed against
the inconvenience and pain associated with injection.
Options for oral prophylaxis include penicillin V, sulfadiazine and macrolides. Success with oral prophylaxis
depends on patient adherence, so clear communication regarding the importance of prophylaxis and how antibiotics
should be taken is critical. Even with optimal adherence, the risk of recurrence is higher in individuals receiving oral
prophylaxis than those receiving intramuscular benzathine penicillin G [26]. This was illustrated in a controlled trial
of 405 children and adolescents with rheumatic fever assigned to receive four weeks of intramuscular benzathine
penicillin G, oral potassium penicillin G or oral sulfadiazine. In the first two years of the study, streptococcal
infections recurred in 7, 20 and 24 percent of patients, respectively; rheumatic fever recurred in 0, 4.8, and 2.7
percent of the patients, respectively.
Therefore, parenteral prophylaxis is preferred for patients at high risk for rheumatic fever recurrence; oral agents are
appropriate for patients at lower risk for rheumatic fever recurrence. Accordingly, switching from intramuscular to
oral prophylaxis once patients have reached young adulthood and have remained free of rheumatic attacks is
appropriate.
The preferred oral agent is penicillin V (table 3). Sulfadiazine or sulfisoxazole is appropriate for patients allergic to
penicillin; this antibiotic class is effective for preventing GAS infection although it cannot be used to achieve
eradication. An oral macrolide such as azithromycin is acceptable for patients allergic to both penicillin and sulfa
drugs.
Prior to initiation of prophylaxis, a full therapeutic course of antibiotic therapy should be given to patients with acute
rheumatic fever to eradicate residual GAS, even if a throat culture is negative (table 1). Prophylactic antibiotics
should be initiated immediately at the end of the therapeutic antibiotic course.
During the course of prophylaxis, patients and their household contacts who develop acute episodes of group A
streptococcal pharyngitis should be evaluated and treated promptly. (See "Treatment and prevention of streptococcal
tonsillopharyngitis".)
Poststreptococcal reactive arthritis — Poststreptococcal reactive arthritis (PSRA) is a reactive arthritis that occurs
after a symptom-free interval following GAS pharyngitis. It differs from the arthritis associated with ARF, as
outlined separately. (See "Clinical manifestations and diagnosis of acute rheumatic fever", section on 'Differential
diagnosis'.)
PSRA can be difficult to distinguish from arthritis associated with ARF on clinical grounds, and a small proportion
of patients with PSRA have been observed to develop valvular heart disease [27,28].
For this reason, some favor administering secondary prophylaxis in the setting of suspected PSRA for up to one year
after the onset of symptoms, although the efficacy of this approach is not well established [4]. Evidence of valvular
disease after one year should prompt continued prophylaxis as outlined in the preceding sections, and it may be
presumed that the presenting symptoms were manifestations of acute rheumatic fever. In the absence of valvular
disease after one year, antibiotic prophylaxis may be discontinued.
SUMMARY AND RECOMMENDATIONS



We recommend that patients with acute rheumatic fever be initiated on antibiotic therapy as delineated for
eradication of streptococcal pharyngitis, whether or not pharyngitis is present at the time of diagnosis (table
1). (Grade 1C). (See 'Treatment' above.)
Patients with severe carditis should be treated with conventional therapy for heart failure. Valve surgery
may be necessary when heart failure due to regurgitant lesions cannot be managed with medical therapy
alone. Aspirin is the mainstay of symptomatic management due to acute rheumatic fever.
(See 'Carditis' above and 'Arthritis and rash' above.)
Prevention of initial attack of rheumatic fever (primary prevention) is accomplished by prompt diagnosis
and antibiotic treatment of group A streptococcal tonsillopharyngitis. (See "Treatment and prevention of
streptococcal tonsillopharyngitis".)




Prevention of recurrent rheumatic fever (secondary prevention) requires prevention of recurrent GAS
pharyngitis. We recommend continuous antimicrobial prophylaxis, rather than recognition and treatment of
acute GAS pharyngitis episodes. (Grade 1B). (See 'Secondary prevention' above.)
In general, prophylaxis for in the setting of carditis should continue until the patient is a young adult (18
years of age), which is usually 10 years from an acute attack with no recurrence (table 2). At the end of a
planned course for secondary prophylaxis, the risk for GAS exposure and severity of valvular disease
should be reviewed. (See 'Duration' above.)
We suggest long acting benzathine penicillin G for secondary prevention of recurrent rheumatic fever
(table 3) (Grade 2B). Switching from intramuscular to oral prophylaxis once patients have reached young
adulthood and have remained free of rheumatic attacks is appropriate. (See 'Antibiotic selection' above.)
We suggest administering secondary prophylaxis in the setting of suspected poststreptococcal reactive
arthritis for up to one year after the onset of symptoms (Grade 2C). Evidence of valvular disease after one
year should prompt continued prophylaxis; otherwise, antibiotic prophylaxis may be discontinued.
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Table 1
Table 2
Table 3