7/8/2017 Acute rheumatic fever: Clinical manifestations and diagnosis - UpToDate

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Acute rheumatic fever: Clinical manifestations and diagnosis

Authors: Andrew Steer, MBBS, PhD, FRACP, Allan Gibofsky, MD, JD, FACP, FCLM
Section Editors: Robert Sundel, MD, Daniel J Sexton, MD
Deputy Editor: Elizabeth TePas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Jan 06, 2017.

INTRODUCTION — Acute rheumatic fever (ARF) is a nonsuppurative sequela that occurs two to four weeks following group A
Streptococcus (GAS) 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 are reviewed here. The epidemiology, pathogenesis, treatment, and prevention of this
disorder are presented separately. (See "Acute rheumatic fever: Epidemiology and pathogenesis" and "Acute rheumatic fever: Treatment
and prevention".)

CLINICAL MANIFESTATIONS

Acute illness — ARF can present with several different clinical findings within weeks of a group A streptococcal (GAS) tonsillopharyngitis
(or streptococcal pyoderma in patients from tropical regions) [1-3]. The possible major and minor manifestations are reviewed here. These
manifestations are used for diagnosis (Revised Jones Criteria) [4,5]. The diagnostic criteria are reviewed below. (See 'Diagnosis' below.)

The five major manifestations (and percent of patients with each) are [4]:

● Carditis and valvulitis (eg, pancarditis) that is clinical or subclinical – 50 to 70 percent

● Arthritis (usually migratory polyarthritis predominantly involving the large joints) – 35 to 66 percent
● Central nervous system involvement (eg, Sydenham chorea) – 10 to 30 percent
● Subcutaneous nodules – 0 to 10 percent
● Erythema marginatum – <6 percent

The four minor manifestations are:

● Arthralgia
● Fever
● Elevated acute phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])
● Prolonged PR interval on electrocardiogram

There are two primary forms of presentation for ARF (table 1). The more common form (approximately 70 to 75 percent of patients) is an
acute febrile illness with joint manifestations and often carditis. The less common form is a neurologic/behavioral disorder with Sydenham
chorea. Joint manifestations are usually absent, and carditis, when present, is often subclinical.

Major manifestations — The major manifestations of ARF include arthritis, carditis, Sydenham chorea, subcutaneous nodules, and
erythema marginatum.

Arthritis — Arthritis usually is the earliest symptomatic manifestation of ARF, generally presenting within 21 days of GAS infection,
although asymptomatic carditis may develop first. It is more common and more severe in teenagers and young adults than in children [6].
Joint pain typically is more prominent than objective signs of inflammation and is almost always transient. However, the arthritis may be
severe enough to severely limit movement.

Generally, the inflammation affects several joints in quick succession, and each joint is inflamed for a day or two to a week [7]. The knees,
ankles, elbows, and wrists are most commonly affected, with the leg joints 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 ARF, and it is also regarded as an additive polyarthritis. The arthritis resolves without treatment in
approximately four weeks, and there is no long-term joint deformity [4].

The natural history of arthritis in ARF is altered by empiric treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or
glucocorticoids. In such cases, arthritis subsides quickly in the joint(s) affected and does not "migrate" to new joints. The diagnosis of ARF
should be reconsidered if joint symptoms do not respond to NSAID treatment within 48 hours.

Patients treated with NSAIDs early in the course of ARF, particularly before the other signs and symptoms of ARF become distinct, may
appear to have monoarthritis rather than polyarthritis. As an example, involvement of a single large joint was common in one series of
patients with ARF who were treated for associated arthritis [7]. In another series including 555 Aboriginal patients in Australia, aseptic
monoarticular arthritis was also described in 17 percent of cases [8]. The presence of monoarthritis rather than polyarthritis can make it
difficult to establish the diagnosis of ARF and determine the need for secondary ARF prophylaxis. Commencement of NSAID therapy can
be delayed if the diagnosis of ARF is suspected but only a single joint is involved, with acetaminophen used for analgesia in the meantime,
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since there is no evidence that temporarily withholding such therapy has any adverse effects. NSAIDs may be commenced once a second
joint is involved and the diagnosis is clear.

Radiography of an affected joint may demonstrate a slight effusion but is usually unremarkable. Thus, radiographic evaluation of affected
joints is not routinely performed. Joint aspiration and synovial fluid evaluation, including culture, is indicated if there is significant effusion of
one joint or septic arthritis is suspected. Analysis of the synovial fluid generally demonstrates sterile inflammatory fluid in patients with
ARF.

Carditis — The carditis associated with ARF is classically considered to be a pancarditis that can involve the pericardium,
epicardium, myocardium, and endocardium [4]. While myocarditis and pericarditis may occur in ARF, the predominant manifestation of
carditis is involvement of the endocardium presenting as a valvulitis, especially of the mitral and aortic valves. It usually presents within
three weeks of GAS infection. The presence of valvulitis is established by auscultatory findings together with echocardiographic evidence
of mitral or aortic regurgitation. The Carey Coombs murmur, a short mid-diastolic murmur heard loudest at the apex, is an indicator of
moderate-severe mitral regurgitation as a result of increased blood flow across the mitral valve during left ventricular filling. Subclinical
carditis can be diagnosed by echocardiography/Doppler studies that reveal mitral or aortic regurgitation in the absence of ausculatory
findings (either because the clinical exam findings are absent or are not recognized). 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 [9]. Chorea has a longer latent period than
other rheumatic manifestations, typically presenting one to eight months after a GAS infection [10], and may occur as an isolated finding. It
is more common in girls and may present as refusal to go to school and self-isolation due to shame and embarrassment. Recurrence of
rheumatic chorea is not uncommon, sometimes associated with pregnancy or the oral contraceptive pill. Most patients with Sydenham
chorea recover fully within six weeks and nearly all within six months, with only rare cases described lasting longer than that. (See
"Sydenham chorea".)

The choreiform movements frequently are more marked on one side, are occasionally unilateral (hemichorea), and cease during sleep.
The movements may be subtle and intermittent, sometimes only seen after a 10- to 15-minute period of quiet observation. 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 maid's sign." The head is often involved, with erratic movements
of the face that resemble grimaces, grins, and frowns. The tongue, if affected, can resemble a "bag of worms" when protruded, and
protrusion cannot be maintained. Chorea disappears with sleep and is made more pronounced by purposeful movements. Diffuse
hypotonia may be present. Neurologic examination fails to reveal sensory losses or involvement of the pyramidal tract.

Emotional changes manifest with outbursts of inappropriate behavior including crying and restlessness. Some patients have features of
obsessive-compulsive disorder (OCD). Halting and jerky speech patterns are also sometimes seen. In rare cases, psychologic
manifestations are severe and may result in transient psychosis.

Erythema marginatum — Erythema marginatum is an evanescent, pink or faintly red, nonpruritic rash involving the trunk and
sometimes the limbs but not the face [11]. When present, it usually occurs early in the course of ARF, but, in some cases, the lesions are
first noticed late in the illness or even during convalescence [12]. In some instances, it persists or recurs after all other manifestations have
resolved. Erythema marginatum most commonly occurs in patients with acute carditis but has been reported in patients with chronic
carditis [7]. It rarely occurs as the sole manifestation of ARF.

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.

Subcutaneous nodules — Subcutaneous nodules in ARF are firm, painless lesions ranging from a few millimeters to 2 cm in size.
They are smaller and shorter lived than the nodules of rheumatoid arthritis. Subcutaneous nodules associated with ARF generally appear
after the first weeks of illness, usually in patients with relatively severe carditis. They rarely appear as the only manifestation of ARF.
Typically, nodules are present for one or more weeks, but they rarely persist for more than a month.

The nodules are usually located over a bony surface or prominence or near tendons (usually extensor surfaces) and are usually
symmetric. The elbows are involved most frequently in both ARF and rheumatoid arthritis. However, ARF nodules occur most commonly
on the olecranon, whereas rheumatoid nodules are usually found 3 to 4 cm distally. The overlying skin is not inflamed and usually can be
moved over the nodules (picture 3) [13]. The number of nodules varies from a single lesion to a few dozen; the average number is three to
four.

Minor manifestations — The minor manifestations of ARF include fever, arthralgia, elevated ESR and CRP, and prolonged PR interval
on electrocardiogram [4].

● Fever – Fever associated with ARF is usually ≥38.5°C orally (101.3°F). However, low-grade fever (≥38°C [100.4°F]) is more common
in high-risk groups, such as the Indigenous Australian population.

● Arthralgia – Arthralgia usually involves several joints (polyarthralgia) when it occurs in patients with ARF. However, it is a common
manifestation in many other rheumatologic disorders and therefore is highly nonspecific.

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● Elevated acute phase reactants – Acute phase reactants are almost always elevated in patients with ARF, except in some patients
with isolated chorea or in those treated with antirheumatic drugs [14]. Typical elevations of acute phase reactants seen in ARF include
an ESR ≥60 mm/hour and CRP ≥3 mg/dL. As with fever, lower levels (ie, ESR ≥30 mm/hour) can be seen in high-risk groups.

● Prolonged PR interval on electrocardiogram – Interpretation of PR prolongation depends upon age and heart rate and is >0.2
seconds in adults. It is important to note that up to one-third of children with uncomplicated streptococcal infections have a prolonged
PR interval [15]. Abnormal atrioventricular conduction is common in ARF, with first degree block the most common abnormality
observed [16]. Severe first-degree block can occasionally lead to a junctional rhythm, and second-degree and complete heart block
can occur [17,18].

Additional features

● Family history – A family history of ARF should heighten the suspicion for ARF in the setting of suggestive features.

● Other findings – Other clinical features seen in patients with ARF include abdominal pain, precordial pain, malaise, epistaxis, rapid
sleeping pulse rate, and tachycardia out of proportion to fever. Laboratory findings include leukocytosis and mild normochromic,
normocytic anemia of chronic inflammation. Complement levels are usually normal in ARF. In contrast, hypocomplementemia is
typically observed in the setting of poststreptococcal glomerulonephritis.

Late sequelae — Rheumatic heart disease (RHD) is the most common and severe sequela of ARF. Jaccoud arthropathy is a rare
complication associated with recurrent episodes of ARF with polyarthritis.

Rheumatic heart disease — RHD usually occurs 10 to 20 years after the original illness, although it may present earlier after a severe
or recurrent episode of ARF. It is the most common cause of acquired valvular disease in the world [19,20]. The mitral valve is more
commonly involved than the aortic valve, and mitral regurgitation is the most common finding of RHD. This may progress to mitral stenosis
in severe cases due to fibrosis and calcification of the mitral valve. In general, valvular damage manifesting as a murmur later in life occurs
in approximately 50 percent of patients who had carditis during the initial episode of ARF [21,22]. RHD is discussed in greater detail
separately. (See "Natural history, screening, and management of rheumatic heart disease".)

Jaccoud arthropathy — Jaccoud arthropathy is a benign, chronic arthropathy that involves loosening and lengthening of periarticular
structures and tendons in the hands and/or feet (picture 4) [23]. The deformities are painless, "correctable" with manipulation, and do not
cause functional impairment. The arthropathy is not associated with active joint inflammation.

DIAGNOSIS — ARF is characterized by group A streptococcal (GAS) infection followed by the clinical manifestations outlined above (see
'Acute illness' above). The diagnosis of ARF is established on clinical grounds using the 2015 Jones Criteria, which are stratified based
upon whether the patient is from a low-risk or a moderate- to high-risk population [4,5]. The diagnostic evaluation includes studies to
establish the diagnosis of GAS infection, evaluate acute phase reactants, and assess cardiac function.

Diagnostic criteria — The initial description of clinical manifestations in 1944, known as the Jones Criteria [24,25], was used by the
American Heart Association (AHA) to establish guidelines for the diagnosis of ARF. These guidelines have been modified over time, most
recently in 2015 [4,26,27].

The 2015 revision of the criteria provides two different sets of criteria: one for low-risk populations (ie, those with a rheumatic fever
incidence ≤2 per 100,000 school-aged children per year or all-age rheumatic heart disease [RHD] prevalence ≤1 per 1000 population) and
one for moderate- to high-risk populations.

The major and minor manifestations included in the Jones Criteria are reviewed above (see 'Acute illness' above). Joint (arthritis or
arthralgia) and cardiac (carditis or prolonged PR interval) manifestations can only be counted once, not twice, as either a major or a minor
criterion.

● Two major manifestations or one major plus two minor are sufficient for diagnosis of an initial episode of ARF in a patient with
evidence of a preceding GAS infection.

● Patients with a history of ARF are at risk of subsequent episodes of ARF with GAS reinfection, and repeat episodes are associated
with a greater likelihood of severe cardiac involvement. In these patients, two major, one major plus two minor, or three minor
manifestations are sufficient for diagnosis of recurrent ARF.

All patients undergo cardiac evaluation, even if they do not present with clinical evidence of carditis. (See 'Cardiac evaluation' below.)

Exceptions — There are three circumstances in which a presumptive diagnosis of ARF can be made without strict adherence to the
above criteria [26]:

● Chorea as the only manifestation. These patients should undergo evaluation for carditis with echocardiogram. (See "Natural history,
screening, and management of rheumatic heart disease", section on 'Acute rheumatic fever'.)

● Indolent carditis as the only manifestation in patients who come to medical attention months after acute GAS infection. An
echocardiogram should be performed in these patients to look for evidence of carditis.

● Recurrent ARF in patients with a history of ARF-associated carditis or RHD. It may be difficult to establish a diagnosis of acute carditis
during an acute attack in the absence of pericarditis or involvement of a new valve. Thus, a presumptive diagnosis of recurrent ARF
may be made with one major or two minor criteria if there is evidence of a recent GAS infection. Caution against using a single clinical
finding (eg, monoarthritis, fever, arthralgia) as a criterion for the diagnosis of recurrent disease is suggested [27].
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Moderate/high-risk populations — Strict adherence to the Jones Criteria in areas of higher prevalence (defined as ARF incidence >2
per 100,000 school-aged children per year or all-age RHD prevalence of >1 per 1000 population) may result in under-diagnosis. This was
illustrated in a report of 555 cases of confirmed ARF among Aboriginal Australians in whom monoarthritis and low-grade fever were
important manifestations [8]. Thus, the criteria are slightly modified for moderate- to high-risk populations as follows [4]:

● The major criterion of arthritis includes monoarthritis or polyarthralgia in addition to polyarthritis. Polyarthralgia should only be
considered as a major manifestation after exclusion of other causes.

● The minor criterion for joint involvement is monoarthralgia rather than polyarthralgia.

● A lower cutoff for fever is used (≥38°C [100.4°F] rather than ≥38.5°C [101.3°F]).

● A lower cutoff for erythrocyte sedimentation rate (ESR) is used (≥30 mm/hour rather than ≥60 mm/hour), although the C-reactive
protein (CRP) cutoff is unchanged (≥3 mg/dL).

Evidence of preceding GAS infection — Confirmation of group A streptococcal (GAS) infection is helpful but not necessary to make the
diagnosis of ARF. 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. Laboratory confirmation is required because the clinical
documentation of an antecedent pharyngitis is unreliable and has an age-related variability. 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 [28]. In
one Australian study, a recent sore throat (suggestive of streptococcal pharyngitis) was reported in 30 percent (39 of 131) of Indigenous
children with ARF, whereas it was reported in 55 percent (10 of 20) of non-Indigenous children [29,30].

Therefore, evidence of prior GAS infection may be sought in one of the following ways:

● Positive throat culture for group A beta-hemolytic streptococci

● Positive rapid streptococcal antigen test
● Elevated or rising antistreptococcal antibody titer – Either antistreptolysin O (ASO) or antideoxyribonuclease B (ADB)

Streptococcal serology is most helpful in the diagnosis of ARF because of the delayed nature of the disease following GAS infection.
Antibody titers are elevated, while culture or detection of the organism is usually no longer possible by the time ARF presents. Throat
cultures are negative in approximately 75 percent of patients by the time manifestations of ARF appear [26]. The rapid streptococcal
antigen test is also commonly negative.

During an infection with GAS, there is a broad immune response to multiple cellular antigens. However, measurement of the antibody
response to streptolysin O and/or deoxyribonuclease B is used most in clinical practice.

Antistreptococcal antibodies have a high sensitivity for the documentation of streptococcal infection in the setting of ARF [31]. Titers vary
with age, season, and geography [32], but published normal values are available for children in the US and children in tropical settings
(table 2 and table 3) [33,34]. Healthy children of elementary school age often have titers of 200 to 300 Todd units/mL because GAS
tonsillopharyngitis is common in this age group, whereas older children and adults who are asymptomatic pharyngeal GAS carriers tend to
have low titers [35].

ASO and ADB titers may be interpreted either by comparison of acute with convalescent titers or against a reference upper limit of normal
(ULN). An increase in titer from acute to convalescent (at least two weeks apart) is considered the best evidence of antecedent GAS
infection [36]. The antibody response of ASO peaks at approximately three to five weeks following GAS pharyngitis, which usually is
during the first to third week of ARF, while ADB titers peak at six to eight weeks [37,38]. 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.

Approximately 80 percent of patients with documented ARF demonstrate a rise in ASO titer above the ULN value for age, defined by the
80th centile, although this cannot be used as a measure of rheumatic activity. In a study in Australia, diagnosis of poststreptococcal
syndromes using an ULN value for ASO had a sensitivity of 73 percent, but the sensitivity increased to >95 percent when ADB was added
to ASO [39]. In the center of one author (AS), an ASO titer is measured first, and, if negative, measurement of ADB is added.

Laboratory studies — Laboratory studies obtained during the initial evaluation include measurement of CRP or ESR to seek evidence of
systemic inflammation and a complete blood count with differential to look for anemia and leukocytosis.

Cardiac evaluation — Electrocardiogram and echocardiogram are performed as part of the initial screening. Portable, handheld
echocardiography is a lower cost option than standard echocardiography in resource-limited settings but must have appropriate capacity
to provide high-quality 2D images, accurate color Doppler, and accurate pulse-wave Doppler measurements [40,41]. The findings are
discussed above. (See 'Carditis' above and "Natural history, screening, and management of rheumatic heart disease", section on 'Acute
rheumatic fever'.)

DIFFERENTIAL DIAGNOSIS — The approach to and differential diagnosis of polyarticular joint pain in children and adults are discussed
separately. (See "Evaluation of the child with joint pain and/or swelling" and "Evaluation of the adult with polyarticular pain".)

Additional manifestations of ARF generally can be distinguished from similar findings in other conditions, although the differences may be
subtle (eg, subcutaneous nodules versus rheumatoid nodules, Sydenham chorea versus other types of chorea, or erythema marginatum
versus erythema annulare). (See "Rheumatoid nodules" and "Overview of chorea" and "Approach to the patient with annular skin
lesions".)
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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) [42-47]. However, 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, must still be considered ARF, especially in children. Defining this reactive arthritis as an
ARF variant has important implications for secondary prophylactic treatment. (See "Reactive arthritis", section on 'Differential diagnosis'.)

The following observations have been used to support the notion that PSRA is a separate disorder [48,49]:

● 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
classic ARF.

● Evidence of carditis is not seen in these patients, and the severity of the arthritis is quite marked.

● Extra-articular manifestations, such as tenosynovitis and renal abnormalities, often are seen in these patients.

● Acute phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [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 genetic or environmental factors.
As an example, variations in the response to aspirin in affected adults may be caused by variations in salicylate levels. Even when patients
with PSRA do not fulfill the Jones Criteria, some investigators regard it as a forme fruste of rheumatic fever requiring similar secondary
prophylaxis [50]. On the other hand, some investigators argue that PSRA is a benign condition without need for prophylaxis [44]. Both the
1992 guidelines and the 2002 update reached the following conclusions [25,32]:

● Although the relationship between PSRA and ARF remains unresolved, patients who fulfill the Jones Criteria should be considered to
have ARF.

● 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.

Treatment of poststreptococcal reactive arthritis is discussed separately. (See "Acute rheumatic fever: Treatment and prevention", section
on 'Poststreptococcal reactive arthritis'.)

REFERRAL — The diagnosis of rheumatic fever can be challenging. Thus, there should be a low threshold to seek opinion from a
pediatric infectious disease specialist and/or pediatric rheumatologist with expertise in ARF. In addition, pediatric cardiology is consulted
for clinical review and an echocardiogram. The pediatric patient with suspected ARF is usually admitted to the hospital for this evaluation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Acute rheumatic fever".)

SUMMARY

● Acute rheumatic fever (ARF) is a nonsuppurative sequela of group A Streptococcus (GAS) pharyngitis that occurs two to four weeks
following infection. (See 'Introduction' above.)

● The five major manifestations (major Jones Criteria) of ARF 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 (minor Jones Criteria) are arthralgia, fever, elevated acute phase reactants,
and prolonged PR interval on electrocardiogram. (See 'Acute illness' above.)

● The diagnosis of ARF is established on clinical grounds. The probability of ARF is high in the setting of GAS infection followed by two
major criteria or one major and two minor criteria. The criteria are modified slightly for patients in moderate- to high-risk populations.
(See 'Diagnosis' 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.)

● ARF causes a pancarditis, affecting the pericardium, epicardium, myocardium, and endocardium, with valvulitis being the most
common clinical presentation. However, the carditis can be subclinical. (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, nonpruritic rash involving the trunk and sometimes the limbs but not the
face (picture 1 and picture 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.)
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● The most common sequela of ARF is rheumatic heart disease (RHD). RHD usually occurs 10 to 20 years after the original illness and
is the most common cause of acquired valvular disease in the world. (See 'Rheumatic heart disease' above and "Natural history,
screening, and management of rheumatic heart disease".)

● Some cases of arthritis occurring after a streptococcal infection are not accompanied by sufficient additional Jones Criteria to meet
diagnostic requirements for ARF. This disorder has been called poststreptococcal reactive arthritis (PSRA). (See 'Poststreptococcal
reactive arthritis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge John B Zabriskie, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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34:383.
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24-hour electrocardiography study. Cardiol Young 2010; 20:620.
17. Clarke M, Keith JD. Atrioventricular conduction in acute rheumatic fever. Br Heart J 1972; 34:472.
18. Reeves BM. Complete heart block complicating Acute Rheumatic Fever. J Paediatr Child Health 2011; 47:844.
19. 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.
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21. Albert DA, Harel L, Karrison T. The treatment of rheumatic carditis: a review and meta-analysis. Medicine (Baltimore) 1995; 74:1.
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disease in Brazilian children and adolescents. Heart 2005; 91:1019.
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24. Jones TD. The diagnosis of rheumatic fever. JAMA 1944; 126:481.
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26. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart
Association. JAMA 1992; 268:2069.

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27. Ferrieri P, Jones Criteria Working Group. Proceedings of the Jones Criteria workshop. Circulation 2002; 106:2521.
28. Veasy LG, Wiedmeier SE, Orsmond GS, et al. Resurgence of acute rheumatic fever in the intermountain area of the United States. N
Engl J Med 1987; 316:421.
29. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis
2004; 4:240.
30. McDonald MI, Towers RJ, Andrews RM, et al. Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian
aboriginal communities where acute rheumatic fever is hyperendemic. Clin Infect Dis 2006; 43:683.
31. Steer AC, Smeesters PR, Curtis N. Streptococcal Serology: Secrets for the Specialist. Pediatr Infect Dis J 2015; 34:1250.
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disease in man. Am J Med 1948; 5:3.
33. Kaplan EL, Rothermel CD, Johnson DR. Antistreptolysin O and anti-deoxyribonuclease B titers: normal values for children ages 2 to
12 in the United States. Pediatrics 1998; 101:86.
34. Steer AC, Vidmar S, Ritika R, et al. Normal ranges of streptococcal antibody titers are similar whether streptococci are endemic to
the setting or not. Clin Vaccine Immunol 2009; 16:172.
35. Sethi S, Kaushik K, Mohandas K, et al. Anti-streptolysin O titers in normal healthy children of 5-15 years. Indian Pediatr 2003;
40:1068.
36. Johnson DR, Kurlan R, Leckman J, Kaplan EL. The human immune response to streptococcal extracellular antigens: clinical,
diagnostic, and potential pathogenetic implications. Clin Infect Dis 2010; 50:481.
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acute pharyngitis. J Pediatr 1974; 84:21.
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tests in acute rheumatic fever and acute glomerulonephritis. Pediatrics 1962; 29:527.
39. Blyth CC, Robertson PW. Anti-streptococcal antibodies in the diagnosis of acute and post-streptococcal disease: streptokinase
versus streptolysin O and deoxyribonuclease B. Pathology 2006; 38:152.
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revealing its distinction from acute rheumatic fever. J Intern Med 1999; 245:261.
46. Mackie SL, Keat A. Poststreptococcal reactive arthritis: what is it and how do we know? Rheumatology (Oxford) 2004; 43:949.
47. Moorthy LN, Gaur S, Peterson MG, et al. Poststreptococcal reactive arthritis in children: a retrospective study. Clin Pediatr (Phila)
2009; 48:174.
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7:683.

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GRAPHICS

Symptoms of febrile illness versus neurologic illness in patients with acute rheumatic fever

Acute febrile illness Neurologic illness (25 to 30%)

Onset two to four weeks after GAS infection Later onset

Fever is common Two to six months after GAS infection
Acute joint symptoms and signs No fever
Carditis Joint manifestations are not a feature
Clinical and subclinical Behavioral disorder and distinctive chorea
Skin manifestations and subcutaneous nodules (both are rare) Carditis >30%
Raised inflammatory markers Often subclinical
Evidence of preceding GAS infection (elevated ASO and anti-DNase B Often normal inflammatory markers
titers) ASO often unhelpful, anti-DNase B may be raised
Dramatic symptomatic response to aspirin and NSAIDS Followed by RHD in approximately 50%
Duration usually <6 weeks
Followed by RHD in approximately 75%

GAS: group A Streptococcus; ASO: antistreptolysin; NSAID: nonsteroidal anti-inflammatory drug; anti-DNase B: antideoxyribonuclease B; RHD: rheumatic
heart disease.

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Erythema marginatum

This image of the back of a patient with acute rheumatic fever shows the
characteristic rash, erythema marginatum. Note the erythematous lesions with
pale centers and rounded or serpiginous margins.

Reproduced with permission from: Binotto MA, Guilherme L, Tanaka AC. Rheumatic
fever. Images Paediatr Cardiol 2002; 11:12. Copyright © 2002 Images in Paediatric
Cardiology.

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Erythema marginatum

A closer view of erythema marginatum in a patient with acute rheumatic fever.

Reproduced with permission from: Binotto MA, Guilherme L, Tanaka AC. Rheumatic
fever. Images Paediatr Cardiol 2002; 11:12. Copyright © 2002 Images in Paediatric
Cardiology.

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Rheumatic subcutaneous nodules

Rheumatic subcutaneous nodules are usually located near tendons or over a

bony surface or prominence (see arrows). The overlying skin is not inflamed and
typically can be moved over the nodules. The diameter varies from a few
millimeters to 1 to 2 centimeters.

Courtesy of Robert Sidbury, MD.

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Jaccoud arthropathy

(A) Ulnar deviation, metacarpophalangeal subluxation, and swan-neck deformities are present. There is also diffuse soft-tissue swelling.
(B) A radiograph shows the deformities, but there is no true joint space narrowing or erosion, which would be expected in a patient with rheumatoid
arthritis with similar hand deformities. This type of deformity in systemic lupus erythematosus is reducible and is caused by tendon laxity, rather than
bony destruction, and may also be seen in post-rheumatic fever arthritis.

© 2016 American College of Rheumatology. Used with permission.

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Upper limit of normal (80 th centile) values for serum streptococcal antibody titers in children in the
United States [1]

Upper limit of normal (international units/mL)

Age (years)
ASO titer ADB titer

2 160 240

3 120 60

4 240

5 160 320

6 240 480

7 640

10 320

11 800

12 480

ASO: anti-streptolysin O; ADB: anti-deoxyribonuclease B.

Reference:
1. Kaplan EL, Rothermel CD, Johnson DR. Antistreptolysin O and anti-deoxyribonuclease B titers: Normal values for children ages 2 to 12 in the United
States. Pediatrics 1998; 101:86.
European Journal of Clinical Microbiology & Infectious Diseases, ASO titer or not? When to use streptococcal serology: A guide for clinicians, Vol. 34, 2015,
p. 845, Parks T, Smeesters PR, Curtis N, Steer AC, with permission of Springer.

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Upper limit of normal (80 th centile) for serum streptococcal antibody titers in children and adults in
tropical settings where group A Streptococcus disease is endemic

Upper limit of normal (international units/mL)

Age group (years)
ASO titer ADB titer

1 to 4 170 366

5 to 14 276 499

15 to 24 238 473

25 to 34 177 390

≥35 127 265

ASO: anti-streptolysin O; ADB: anti-deoxyribonuclease B.

Adapted with permission from: Steer AC, Vidmar S, Ritika R, et al. Normal ranges of streptococcal antibody titers are similar whether streptococci are
endemic to the setting or not. Clin Vaccine Immunol 2009; 16:172. Copyright © 2009 American Society for Microbiology.

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Contributor Disclosures
Andrew Steer, MBBS, PhD, FRACP Nothing to disclose Allan Gibofsky, MD, JD, FACP, FCLM Nothing to disclose Robert Sundel,
MD Nothing to disclose Daniel J Sexton, MD Grant/Research/Clinical Trial Support: Centers for Disease Control and Prevention;
National Institutes of Health [Healthcare epidemiology]. Consultant/Advisory Boards: Sterilis [Medical waste disposal]. Equity
Ownership/Stock Options: Magnolia Medical Technologies [Medical diagnostics (Blood culture techniques)]. Other Financial Interest:
Johnson & Johnson [Mesh-related infections]. Elizabeth TePas, MD, MS Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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