Rheumatic Fever
ETIOLOGY.
There is considerable evidence to support the link between GAS
upper respiratory tract infections and acute rheumatic fever and
rheumatic heart disease. As many as ⅔ of the patients with an
acute episode of rheumatic fever have a history of an upper
respiratory tract infection several weeks before, and the peak age
and seasonal incidence of acute rheumatic fever closely parallel
those of GAS infections. Patients with acute rheumatic fever
almost always have serologic evidence of a recent GAS infection.
Antimicrobial therapy that eliminates GAS from the pharynx also
prevents initial episodes of acute rheumatic fever, and long-term,
continuous prophylaxis that prevents GAS pharyngitis also
prevents recurrences of acute rheumatic fever.Not all of the
serotypes of GAS can cause rheumatic fever. When some strains
(M type 4) were present in a very susceptible rheumatic
population, no recurrences of rheumatic fever occurred. In
contrast, episodes of pharyngitis with other serotypes prevalent in
the same population were associated with frequent recurrences. In
addition, certain serotypes of GAS (M types 1, 3, 5, 6, 18, 24) are
more frequently isolated from patients with acute rheumatic fever
than are other serotypes.
PATHOGENESIS. The cytotoxicity theory suggests that a GAS
toxin may be involved in the pathogenesis of acute rheumatic fever
and rheumatic heart disease. GAS produces several enzymes that
are cytotoxic for mammalian cardiac cells, such as streptolysin O,
which has a direct cytotoxic effect on mammalian cells in tissue
culture. An immune-mediated pathogenesis for acute rheumatic
fever and rheumatic heart disease has been suggested by the
clinical similarity of acute rheumatic fever to other illnesses
produced by immunopathogenic processes and by the latent period
between the GAS infection and the acute rheumatic fever. The
antigenicity of a large variety of GAS products and constituents, as
well as the immunologic cross reactivity between GAS
components and mammalian tissues, also lends support to this
hypothesis. Common antigenic determinants are shared between
certain components of GAS (M protein, protoplast membrane, cell
wall group A carbohydrate, capsular hyaluronate) and specific
mammalian tissues (e.g., heart, brain, joint).
CLINICAL MANIFESTATIONS AND DIAGNOSIS.
Because no clinical or laboratory finding is pathognomonic for
acute rheumatic fever, T. Duckett Jones in 1944 proposed
guidelines to aid in diagnosis and to limit overdiagnosis. The
Jones criteria, as revised in 1992 by the American Heart
Association are intended only for the diagnosis of the initial attack
of acute rheumatic fever and not for recurrences. There are 5
major and 4 minor criteria and an absolute requirement for
evidence (microbiologic or serologic) of recent GAS infection. The
diagnosis of acute rheumatic fever can be established by the Jones
criteria when a patient fulfills 2 major criteria or 1 major and 2
minor criteria and meets the absolute requirement. There are 3
circumstances in which the diagnosis of acute rheumatic fever can
be made without strict adherence to the Jones criteria. Chorea may
occur as the only manifestation of acute rheumatic fever. Similarly,
indolent carditis may be the only manifestation in patients who 1st
come to medical attention months after the onset of acute
rheumatic fever. Finally, although most patients with recurrences
of acute rheumatic fever fulfill the Jones criteria, some may not.
Guidelines for the Diagnosis of Initial Attack of Rheumatic
Fever (Jones Criteria, Updated 1992)
SUPPORTING
EVIDENCE OF
ANTECEDENT
MAJOR
MINOR
GROUP A
MANIFESTATIONS MANIFESTATION STREPTOCOCCA
[*]
S
L INFECTION
Carditis
Positive throat
Clinical features:
culture or rapid
streptococcal
antigen test
Polyarthritis
Arthralgia
Fever
Elevated or
increasing
streptococcal
antibody titer
Erythema marginatum Laboratory
features:
Subcutaneous nodules Elevated acute phase
reactants:
Erythrocyte
sedimentation rate
C-reactive protein
Prolonged PR
interval
Chorea
MIGRATORY POLYARTHRITIS.
Arthritis occurs in about 75% of patients with acute rheumatic
fever and typically involves larger joints, particularly the knees,
ankles, wrists, and elbows. Involvement of the spine, small joints
of the hands and feet, or hips is uncommon. Rheumatic joints are
generally hot, red, swollen, and exquisitely tender; even the
friction of bedclothes is uncomfortable. The pain can precede and
can appear to be disproportionate to the other findings. The joint
involvement is characteristically migratory in nature; a severely
inflamed joint can become normal within 1–3 days without
treatment, as 1 or more other large joints become involved. Severe
arthritis can persist for several weeks in untreated patients.
Monoarticular arthritis is unusual unless anti-inflammatory therapy
is initiated prematurely, aborting the progression of the migratory
polyarthritis. If a child with fever and arthritis is suspected of
having acute rheumatic fever, it frequently is useful to withhold
salicylates and observe for migratory progression. A dramatic
response to even small doses of salicylates is another characteristic
feature of the arthritis, and the absence of such a response should
suggest an alternative diagnosis. Rheumatic arthritis is typically
not deforming. Synovial fluid in acute rheumatic fever usually has
10,000–100,000 white blood cells/mm3 with a predominance of
neutrophils, a protein of about 4 g/dL, a normal glucose, and forms
a good mucin clot. Frequently, arthritis is the earliest manifestation
of acute rheumatic fever and may correlate temporally with peak
antistreptococcal antibody titers. There is an apparent inverse
relationship between the severity of arthritis and the severity of
cardiac involvement.
CARDITIS.
Carditis and resultant chronic rheumatic heart disease are the most
serious manifestations of acute rheumatic fever and account for
essentially all of the associated morbidity and mortality.
Rheumatic carditis is characterized by pancarditis, with active
inflammation of myocardium, pericardium, and endocardium.
Cardiac involvement during acute rheumatic fever varies in
severity from fulminant, potentially fatal exudative pancarditis to
mild, transient cardiac involvement. Endocarditis (valvulitis),
which manifests by 1 or more cardiac murmurs, is a universal
finding in rheumatic carditis, whereas the presence of pericarditis
or myocarditis is variable. Myocarditis and/or pericarditis without
evidence of endocarditis is rarely due to rheumatic heart disease.
Most cases consist of either isolated mitral valvular disease or
combined aortic and mitral valvular disease. Isolated aortic or
right-sided valvular involvement is uncommon. Serious and longterm illness is related entirely to valvular heart disease as a
consequence of a single attack or recurrent attacks of acute
rheumatic fever. Valvular insufficiency is characteristic of both
acute and convalescent stages of acute rheumatic fever, whereas
valvular stenosis usually appears several years or even decades
after the acute illness. In developing countries, however, where
acute rheumatic fever often occurs at a younger age, mitral stenosis
and aortic stenosis may develop sooner after acute rheumatic fever
than in developed countries, and can occur in young children.
Acute rheumatic carditis usually presents as tachycardia and
cardiac murmurs, with or without evidence of myocardial or
pericardial involvement. Moderate to severe rheumatic carditis can
result in cardiomegaly and congestive heart failure with
hepatomegaly and peripheral and pulmonary edema.
Echocardiographic findings include pericardial effusion, decreased
ventricular contractility, and aortic and/or mitral regurgitation.
Mitral regurgitation is characterized by a high-pitched apical
holosystolic murmur radiating to the axilla. In patients with
significant mitral regurgitation, this may be associated with an
apical mid-diastolic murmur of relative mitral stenosis. Aortic
insufficiency is characterized by a high-pitched decrescendo
diastolic murmur at the upper left sternal border.
Carditis occurs in about 50–60% of all cases of acute rheumatic
fever. Recurrent attacks of acute rheumatic fever in patients who
had carditis with the initial attack are associated with high rates of
carditis. The major consequence of acute rheumatic carditis is
chronic, progressive valvular disease, particularly valvular
stenosis, which can require valve replacement and predispose to
infective endocarditis.
CHOREA.
Sydenham chorea occurs in about 10–15% of patients with acute
rheumatic fever and usually presents as an isolated, frequently
subtle, neurologic behavior disorder. Emotional lability,
incoordination, poor school performance, uncontrollable
movements, and facial grimacing, exacerbated by stress and
disappearing with sleep, are characteristic. Chorea occasionally is
unilateral. The latent period from acute GAS infection to chorea is
usually longer than for arthritis or carditis and can be months.
Onset can be insidious, with symptoms being present for several
months before recognition. Clinical maneuvers to elicit features of
chorea include (1) demonstration of milkmaid's grip (irregular
contractions of the muscles of the hands while squeezing the
examiner's fingers), (2) spooning and pronation of the hands when
the patient's arms are extended, (3) wormian darting movements of
the tongue upon protrusion, and (4) examination of handwriting to
evaluate fine motor movements. Diagnosis is based on clinical
findings with supportive evidence of GAS antibodies. However, in
patients with a long latent period from the inciting streptococcal
infection, antibody levels may have declined to normal. Although
the acute illness is distressing, chorea rarely, if ever, leads to
permanent neurologic sequelae.
ERYTHEMA MARGINATUM.
Erythema marginatum is a rare (<3% of patients with acute
rheumatic fever) but characteristic rash of acute rheumatic fever. It
consists of erythematous, serpiginous, macular lesions with pale
centers that are not pruritic. It occurs primarily on the trunk and
extremities, but not on the face, and it can be accentuated by
warming the skin.
SUBCUTANEOUS NODULES.
Subcutaneous nodules are a rare (≤1% of patients with acute
rheumatic fever) and consist of firm nodules approximately 1 cm
in diameter along the extensor surfaces of tendons near bony
prominences. There is a correlation between the presence of these
nodules and significant rheumatic heart disease.
Minor Manifestations.
The 2 clinical minor manifestations are arthralgia (in the absence
of polyarthritis as a major criterion) and fever (typically
temperature ≥102°F and occurring early in the course of illness).
The 2 laboratory minor manifestations are elevated acute-phase
reactants (e.g., C-reactive protein, erythrocyte sedimentation rate)
and prolonged PR interval on electrocardiogram (1st degree heart
block). However, a prolonged PR interval alone does not constitute
evidence of carditis or predict long-term cardiac sequelae.
Recent Group A Streptococcus Infection.
An absolute requirement for the diagnosis of acute rheumatic fever
is supporting evidence of a recent GAS infection. Acute rheumatic
fever typically develops 2–4 wk after an acute episode of GAS
pharyngitis at a time when clinical findings of pharyngitis are no
longer present and when only 10–20% of the throat culture or rapid
streptococcal antigen test results are positive. One third of patients
have no history of an antecedent pharyngitis. Therefore, evidence
of an antecedent GAS infection is usually based on elevated or
increasing serum antistreptococcal antibody titers. A slide
agglutination test (Streptozyme) has been introduced, and it is
purported to detect antibodies against 5 different GAS antigens.
Although this test is rapid, relatively simple to perform, and widely
available, it is less standardized and less reproducible than other
tests and should not be used as a diagnostic test for evidence of an
antecedent GAS infection. If only a single antibody is measured
(usually antistreptolysin O), only 80–85% of patients with acute
rheumatic fever have an elevated titer; however, 95–100% have an
elevation if 3 different antibodies (antistreptolysin O, anti-DNase
B, antihyaluronidase) are measured. Therefore, when acute
rheumatic fever is suspected clinically, multiple antibody tests are
performed. Except for patients with chorea, clinical findings of
acute rheumatic fever generally coincide with peak
antistreptococcal antibody responses. Most patients with chorea
have elevation of antibodies to 1 or more GAS antigens, although
these antibodies may be waning. The diagnosis of acute rheumatic
fever should not be made in patients with elevated or increasing
streptococcal antibody titers who do not fulfill the Jones criteria
because such titer changes may be coincidental. This is most often
true in younger, school-aged children, many of whom have GAS
pyoderma in the summer or unrelated GAS pharyngitis during the
winter and spring months.
Differential Diagnosis. .
Differential Diagnosis of Acute Rheumatic Fever
ARTHRITIS
CARDITIS
CHOREA
Rheumatoid arthritis
Viral
Huntington chorea
myocarditis
Reactive arthritis (e.g.,
Shigella, Salmonella,
Yersinia)
Viral
pericarditis
Wilson disease
Serum sickness
Infective
endocarditis
Systemic lupus
erythematosus
Sickle cell disease
Kawasaki
disease
Cerebral palsy
Malignancy
Congenital
heart disease
Tics
Systemic lupus
erythematosus
Mitral valve
prolapse
Hyperactivity
ARTHRITIS
Lyme disease (Borrelia
burgdorferi)
CARDITIS
Innocent
murmurs
CHOREA
Gonococcal infection
(Neisseria gonorrhoeae)
TREATMENT.
All patients with acute rheumatic fever should be placed on bed
rest and monitored closely for evidence of carditis. They can be
allowed to ambulate as soon as the signs of acute inflammation
have subsided. However, patients with carditis require longer
periods of bed rest.
Antibiotic Therapy.
Once the diagnosis of acute rheumatic fever has been established
and regardless of the throat culture results, the patient should
receive 10 days of orally administered penicillin or erythromycin,
or a single intramuscular injection of benzathine penicillin to
eradicate GAS from the upper respiratory tract. After this initial
course of antibiotic therapy, the patient should be started on longterm antibiotic prophylaxis.
Anti-Inflammatory Therapy.
Anti-inflammatory agents (e.g., salicylates, corticosteroids) should
be withheld if arthralgia or atypical arthritis is the only clinical
manifestation of presumed acute rheumatic fever. Premature
treatment with 1 of these agents may interfere with the
development of the characteristic migratory polyarthritis and thus
obscure the diagnosis of acute rheumatic fever. Agents such as
acetaminophen can be used to control pain and fever while the
patient is being observed for more definite signs of acute rheumatic
fever or for evidence of another disease.
Patients with typical migratory polyarthritis and those with carditis
without cardiomegaly or congestive heart failure should be treated
with oral salicylates. The usual dose of aspirin is 100 mg/kg/day in
4 divided doses PO for 3–5 days, followed by 75 mg/kg/day in 4
divided doses PO for 4 wk. Determination of the serum salicylate
level is not necessary unless the arthritis does not respond or signs
of salicylate toxicity (tinnitus, hyperventilation) develop. There is
no evidence that nonsteroidal anti-inflammatory agents are any
more effective than salicylates.
Patients with carditis and cardiomegaly or congestive heart failure
should receive corticosteroids. The usual dose of prednisone is 2
mg/kg/day in 4 divided doses for 2–3 wk followed by a tapering of
the dose that reduces the dose by 5 mg/24 hr every 2–3 days. At
the beginning of the tapering of the prednisone dose, aspirin should
be started at 75 mg/kg/day in 4 divided doses for 6 wk. Supportive
therapies for patients with moderate to severe carditis include
digoxin, fluid and salt restriction, diuretics, and oxygen. The
cardiac toxicity of digoxin is enhanced with myocarditis.
Sydenham Chorea. Because chorea often occurs as an isolated
manifestation after the resolution of the acute phase of the disease,
anti-inflammatory agents are usually not indicated. Sedatives may
be helpful early in the course of chorea; phenobarbital (16–32 mg
every 6–8 hr PO) is the drug of choice. If phenobarbital is
ineffective, then haloperidol (0.01–0.03 mg/kg/24 hr divided bid
PO) or chlorpromazine (0.5 mg/kg every 4–6 hr PO) should be
initiated.
COMPLICATIONS.
 The arthritis and chorea of acute rheumatic fever resolve
completely without sequelae. Therefore, the long-term
sequelae of rheumatic fever are usually limited to the heart
Patients with cardiac valvular disease secondary to acute rheumatic
fever are at increased risk for developing infective endocarditis
during episodes of transient bacteremia. The antibiotic regimens
used to prevent recurrences of acute rheumatic fever are
inadequate for protection against infective endocarditis. The
current recommendations of the American Heart Association
regarding infective endocarditis prophylaxis should be followed).
Patients with residual rheumatic valvular disease do not always
require endocarditis prophylaxis. The importance of good dental
hygiene in the prevention of infective endocarditis should also be
stressed. Patients who have had rheumatic fever but have no
evidence of residual valvular disease do not require endocarditis
prophylaxis.
PROGNOSIS.
The prognosis for patients with acute rheumatic fever depends on
the clinical manifestations present at the time of the initial episode,
the severity of the initial episode, and the presence of recurrences.
Approximately 70% of the patients with carditis during the initial
episode of acute rheumatic fever recover with no residual heart
disease; the more severe the initial cardiac involvement, the greater
the risk for residual heart disease. Patients without carditis during
the initial episode are unlikely to have carditis with recurrences. In
contrast, patients with carditis during the initial episode are likely
to have carditis with recurrences, and the risk for permanent heart
damage increases with each recurrence. Patients who have had
acute rheumatic fever are susceptible to recurrent attacks following
reinfection of the upper respiratory tract with GAS. Therefore,
these patients require long-term continuous chemoprophylaxis.
Before antibiotic prophylaxis was available, 75% of patients who
had an initial episode of acute rheumatic fever had 1 or more
recurrences during their lifetime. These recurrences were a major
source of morbidity and mortality. The risk of recurrence is highest
immediately after the initial episode and decreases with time.
Approximately 20% of patients who present with “pure” chorea
who are not given secondary prophylaxis develop rheumatic heart
disease within 20 yr. Therefore, patients with chorea, even in the
absence of other manifestations of rheumatic fever, require longterm antibiotic prophylaxis.
PREVENTION.
Prevention of both initial and recurrent episodes of acute rheumatic
fever depends on controlling GAS infections of the upper
respiratory tract. Prevention of initial attacks (primary prevention)
depends on identification and eradication of the GAS that produces
episodes of acute pharyngitis. Individuals who have already
suffered an attack of acute rheumatic fever are particularly
susceptible to recurrences of rheumatic fever with any subsequent
GAS upper respiratory tract infection, whether or not they are
symptomatic. Therefore, these patients should receive continuous
antibiotic prophylaxis to prevent recurrences (secondary
prevention).
Primary Prevention.
Appropriate antibiotic therapy instituted before the 9th day of
symptoms of acute GAS pharyngitis is highly effective in
preventing 1st attacks of acute rheumatic fever from that episode.
However, about ⅓ of patients with acute rheumatic fever do not
recall a preceding episode of pharyngitis.
Secondary Prevention.
Secondary prevention is directed at preventing acute GAS
pharyngitis in patients at substantial risk of recurrent acute
rheumatic fever. Secondary prevention requires continuous
antibiotic prophylaxis, which should begin as soon as the diagnosis
of acute rheumatic fever has been made and immediately after a
full course of antibiotic therapy has been completed. Because
patients who have had carditis with their initial episode of acute
rheumatic fever are at a relatively high risk for having carditis with
recurrences and for sustaining additional cardiac damage, they
should receive antibiotic prophylaxis well into adulthood and
perhaps for life.Patients who did not have carditis with their initial
episode of acute rheumatic fever have a relatively low risk for
carditis with recurrences. Antibiotic prophylaxis may be
discontinued in these patients when they reach their early 20s and
after at least 5 yr have elapsed since their last episode of acute
rheumatic fever. The regimen of choice for secondary prevention is
a single intramuscular injection of benzathine penicillin G (1.2
million IU) every 4 wk. In compliant patients, continuous oral
antimicrobial prophylaxis can be used. Penicillin V given twice
daily and sulfadiazine given once daily are equally effective when
used in such patients. For the exceptional patient who is allergic to
both penicillin and sulfonamides, erythromycin given twice daily
may be used. The duration of secondary prophylaxis is noted in
Table.
-- Chemoprophylaxis for Recurrences of Acute Rheumatic
Fever
DRUG
DOSE
ROUTE
Penicillin G
1.2 million U, every 4 wk[*] Intramuscular
benzathine
OR
Penicillin V
250 mg, twice a day
Oral
0.5 g, once a day for
patients ≤27 kg (≤60 lb)
Oral
OR
Sulfadiazine or
sulfisoxazole
DRUG
DOSE
1.0 g, once a day for
patients >27 kg (>60 lb)
ROUTE
FOR PEOPLE WHO ARE ALLERGIC TO PENICILLIN
AND SULFONAMIDE DRUGS
Erythromycin
250 mg, twice a day
Oral
Duration of Prophylaxis for People Who Have Had Acute
Rheumatic Fever: Recommendations of the American Heart
Association
CATEGORY
DURATION
Rheumatic fever without
5 yr or until 21 yr of age,
carditis
whichever is longer
Rheumatic fever with carditis
but without residual heart
disease (no valvular disease[*])
10 yr or well into adulthood,
whichever is longer
Rheumatic fever with carditis
and residual heart disease
(persistent valvular disease[*])
At least 10 yr since last episode
and at least until 40 yr of age;
sometimes lifelong prophylaxis