RHEUMATIC FEVER

Definition

 Rheumatic fever is an inflammatory disease that follows

infection with certain strains of group A streptococci.
 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
 The disease presents with various manifestations that
may include arthritis, carditis, chorea, subcutaneous
nodules, and erythema marginatum.
 The disease affects the heart, joints, central nervous
system, and subcutaneous tissue.

Epidemiology

 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
 Among indigenous groups and developing nations, over
15 million people are estimated to have rheumatic heart
disease.
 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
 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

Etiology
 Epidemiologic studies suggest an individual propensity to
develop rheumatic fever, a nonsuppurative complication
of group A streptococcal infection of the upper respiratory
tract must occur, which occurs most commonly in children
5 to 15 years of age.
 Streptococcus pyogenes (-hemolysis group A
streptococci) cause both superficial infections (e.g.
pharyngitis, impetigo) and invasive diseases.
 Rheumatic fever occurs in 3% of patients who carry an
infecting strain for more than 3 weeks after
convalescence, whereas persons carrying the organism
for less than 3 weeks have an incidence of only 0.3%.
 Patients with streptococcal infections and a history of
previous rheumatic fever have a 5 to 50% greater
incidence of rheumatic fever than do patients with no
prior history of the disease; this tendency declines with
age.
 Environmental factors (latitude, altitude, humidity),
nutrition, crowding, and age appear to influence the
incidence of rheumatic fever, probably because the same
factors influence the incidence of streptococcal infection.
 Pathologic changes are found throughout the body in
connective tissue and around small blood vessels.
 The pathognomonic lesion of rheumatic fever is the
Aschoff body, an inflammatory lesion associated with
swelling and fragmentation of collagen fibers and
alterations in the staining characteristics of connective
tissue.
 Endocarditis produces a verrucous valvitis that may heal
with fibrous thickening and adhesions of valve
commissures and chordae tendineae, resulting in variable
degrees of valve stenosis and insufficiency.
 The mitral and aortic valves are affected most commonly,
the tricuspid less frequently, and the pulmonary valve
rarely.
 Pathologic changes in the joints consist of exudation with
edema of synovial membranes, focal necrosis in the joint
 capsule, edema and inflammation in periarticular tissue,
and joint effusion.
 Subcutaneous nodules seen during the acute phase of the
disease resemble Aschoff bodies and are granulomas with
localized areas of fibrinoid swelling of collagen and
perivascular infiltration with large cells, pale nuclei, and
prominent nucleoli.
 "Rheumatic pneumonia" consists of exudative and
inflammatory changes without Aschoff bodies.

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
 Streptococcal pharyngitis has been the only streptococcal
infection associated with ARF.
 RF 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
 Molecular mimicry: As a result of molecular mimicry,
antibodies directed against GAS antigens crossreact with
host antigens
 In addition to the role of antibody, observations suggest a
role for cellular immunity in molecular mimicry in ARF.
 Carditis: Streptococcal M protein and N-acetyl-beta-D-
glucosamine (NABG, the immunodominant carbohydrate
antigen of GAS) share epitopes with myosin
 Chorea: Molecular mimicry may also be involved in the
development of Sydenham chorea
 In Sydenham chorea, the antibodies bind to
lysoganglioside on the neuronal cell surface, where they
are capable of triggering a signaling cascade
 From a pathophysiologic viewpoint, the available data
suggest involvement of the basal ganglia and cortical
structures
 In ARF patients with Sydenham chorea, there are common
antibodies to antigens found in the S. pyogenes cell
membrane and the caudate nucleus of the brain, further
supporting the concept of an aberrant autoimmune
response as being responsible for ARF.
 Genetic susceptibility: 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.
 Streptolysin O is toxic to a wide variety of cell types,
including myocardium.
 Other extracellular products that may play a role in tissue
damage and spread of organisms through tissue planes
include a family of deoxyribonucleases (DNAses A to D),
hyaluronidase, and streptokinase).

Clinical features

 Pharyngitis usually occurs two to four weeks before the

onset of ARF symptoms.
 The clinical illness is self-limited, but damage to the
valves may be chronic and progressive, resulting in
cardiac decompensation and death.
 Acute rheumatic fever occurs most frequently in children
from four to nine years of age.
 The onset of the disease usually is characterized by an
acute febrile illness that may manifest itself in one of
several ways:
1) Migratory arthritis predominantly involving the large
joints
2) Carditis and valvulitis
3) Central nervous system involvement (e.g. Sydenham
chorea)
4) Rash
5) Some combination of the above
 Arthritis: In the classic, untreated case, the arthritis of
rheumatic fever affects several joints in quick succession,
each for a short time
 The knees, ankles, elbows, and wrists are affected most
commonly, with the leg joints typically being 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" often are used
to describe the polyarthritis of rheumatic fever.
 Joint involvement is more common and more severe in
teenagers and young adults than in children.
 Arthritis usually is the earliest symptomatic manifestation
of ARF, although asymptomatic carditis may come first.
 Typically, inflammation is present in six to 16 joints, and
each joint is inflamed for no more than one week
 Carditis: Rheumatic fever produces a pancarditis
affecting the pericardium, epicardium, myocardium, and
endocardium.
 Cardiac manifestations may be subtle and include a
variety of signs or symptoms: Mild to moderate chest
discomfort, pleuritic chest pain, or a pericardial friction
rub are indications of pericarditis.
 Physical examination may reveal new or changing
murmurs.
 Mitral regurgitation is the most common finding.
 The combination of severe valvular damage and
myocardial dysfunction from myocarditis can lead to heart
failure
 Chorea: Sydenham chorea (SC), also known as St. Vitus
dance, St. Johannis' chorea, chorea minor, and rheumatic
chorea is a neurologic disorder consisting of abrupt,
purposeless, nonrhythmic involuntary movements,
muscular weakness, and emotional disturbances
 The movements commonly are more marked on one side,
are occasionally unilateral (hemichorea), and cease during
sleep.
 Muscle weakness is best revealed by asking the patient to
squeeze the examiner's hands; the pressure of the
patient's grip increases and decreases continuously and
capriciously, a phenomenon known as relapsing grip or
"milking sign."
 Emotional changes manifest themselves in outbursts of
inappropriate behavior, including crying and restlessness.
 In rare cases, the psychologic manifestations may be
severe and may result in transient psychosis.
 Neurologic examination fails to reveal sensory losses or
involvement of the pyramidal tract.
 Diffuse hypotonia may be present
 Subcutaneous nodules: These skin lesions in ARF have
many identifying characteristics
 The nodules are firm and painless.
 The overlying skin is not inflamed and usually can be
moved over the nodules.
 The diameter varies from a few millimeters to one or two
centimeters.
 The nodules most commonly are located over a bony
surface or prominence or near tendons.
 The number of nodules varies from a single lesion to a few
dozen and averages three or four; when numerous, the
nodules usually are symmetric.
 Nodules are present for one or more weeks, rarely for
more than a month.
 They are smaller and more short-lived than the nodules of
rheumatoid arthritis.
 Furthermore, although the elbows are involved most
frequently in both diseases, rheumatic fever nodules are
more common on the olecranon, whereas rheumatoid
nodules usually are found 3 to 4 cm distally.
 Rheumatic subcutaneous nodules generally appear only
after the first weeks of illness and usually only in patients
with carditis.
 In contemporary outbreaks of ARF, nodules have been the
least common manifestation, appearing in no more than 5
percent of patients
 Erythema marginatum: Erythema marginatum is an
evanescent, non-pruritic rash, pink or faintly red, usually
affecting the trunk and sometimes the proximal parts or
the limbs, but not the face
 Because the margin of the lesion usually is continuous,
making a ring, it also is known as "erythema annulare"
 Individual lesions may appear, disappear, and even
reappear in a matter of hours.
 A hot bath or shower may make them more evident or
may even reveal them for the first time.
 Erythema marginatum usually occurs early in the disease.
 It often persists or recurs when all other manifestations of
disease have disappeared.

Diagnosis

Jones criteria

 If supported by evidence of a preceding group A

streptococcal infection, the presence of two major
manifestations or of one major and two minor
manifestations is indicative of a high probability of acute
rheumatic fever
 Major manifestations: The five major manifestations
are:
1. Carditis
2. Polyarthritis
3. Chorea
4. Erythema marginatum
5. Subcutaneous nodules
 Minor manifestations: The four minor manifestations
are:
 Clinical findings
1. Arthralgia
2. Fever
 Laboratory findings
1. Elevated acute phase reactants (erythrocyte
sedimentation rate, C-reactive protein)
2. Prolonged PR interval
 Evidence of preceding streptococcal infection: Any
one of the following is considered adequate evidence of
infection.
1. Positive throat culture for group A beta-hemolytic
streptococci or positive rapid streptococcal antigen test
2. Elevated or rising streptococcal antibody titer, most
often antistreptolysin O
 Exceptions: The 1992 guidelines noted three settings in
which the diagnosis of acute rheumatic fever could be
made without strict adherence to the Jones criteria
 In each setting, the diagnosis is presumptive until other
causes have been excluded.
1. Chorea as the only manifestation
2. Indolent carditis as the only manifestation in patients
who come to medical attention months after the acute
infection
3. Recurrent rheumatic fever in patients with a history of
rheumatic fever or rheumatic heart disease

Treatment

 Three major goals in the treatment of acute rheumatic

fever are:
1. Symptomatic relief of acute disease manifestations
2. Eradication of the group A beta-hemolytic
streptococcus
3. Prophylaxis against future infection to prevent
recurrent cardiac disease
 There is no therapy that slows progression of valvular
damage in patients with ARF.

Symptomatic relief

 The mainstay of treatment for acute rheumatic fever

remains antiinflammatory agents, most commonly aspirin
 Dramatic improvement in symptoms such as arthritis and
fever typically is seen after the start of therapy.
 Usually 80 to 100 mg/kg per day in children and 4 to 8
g/day in adults are required.
 Carditis: Severe carditis is marked by the presence of
significant cardiomegaly, congestive heart failure, or
third-degree heart block.
 Such patients should be treated with conventional therapy
for heart failure.
 Patients with severe carditis are often treated with
corticosteroids, but studies of the effects of
corticosteroids in the treatment of rheumatic carditis have
shown conflicting results
 When corticosteroids are used, the usual dose is 2 mg/kg
per day of oral prednisone for the first one to two weeks.
 Depending upon the clinical and laboratory response, the
dose is then tapered over the next two weeks.
 During this time, aspirin may be added in the dose
recommended above to achieve a serum concentration of
20 to 30mg/dL.
 Valve surgery may be necessary when heart failure is due
to regurgitant lesions that cannot be adequately managed
with medical therapy
 Surgical outcomes are generally better if valve surgery
can be performed when carditis is quiescent
 Valve repair, if feasible, is preferred to 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

Antibiotic therapy

 Antibiotic therapy with penicillin should be started and

maintained for at least 10 days, regardless of the
presence or absence of pharyngitis at the time of
diagnosis.
 The dose of oral penicillin V is that recommended for the
eradication of streptococcal pharyngitis: 250 mg two to
three times daily for children 500 mg two to three times
daily for adults.
 A depot penicillin, such as benzathine penicillin G, in one
single intramuscular dose should be given if compliance is
 an issue: 600,000 units for children who weigh ≤ 27 kg
1.2 million units for children who weigh >27 kg and adults
 Individuals who are allergic to penicillin can be treated
with erythromycin 40 mg/kg per day (maximum dose of
1000 mg) divided into two to four doses.
 A 10-day course of a narrow spectrum oral cephalosporin
is also acceptable.
 In addition, the throats of all family contacts should be
cultured; penicillin therapy is initiated if they are positive
for beta-hemolytic streptococci.

Antibiotic prophylaxis

 The goal of prophylaxis against group A streptococcal

infection is to prevent recurrence of ARF.
 Recurrence is most common within two years of the
original attack but can happen at any time.
 Recurrence rates decrease with increasing age
 Antibiotic prophylaxis should be started immediately after
resolution of the acute episode.
 Either oral or parenteral therapy can be given
 Acceptable oral regimens include:
 Penicillin V potassium 400,000 units (250 mg) twice per
day
 Sulfadiazine 500 mg per day for children ≤ 27 kg and
1000 mg per day for children >27 kg and adults.
 The classic parenteral regimen is benzathine penicillin G
1.2 million units intramuscularly every four weeks
 However, injections every three weeks may be more
effective in preventing recurrences of acute rheumatic
fever
 Individuals who are allergic to penicillin and sulfadiazine
can be treated with oral erythromycin 250 mg twice daily
 Duration of prophylaxis: The duration of prophylaxis is not
well defined, and depends upon the number of previous
attacks, the time lapsed since the last attack, the risk of
exposure to streptococcal infections, the age of the
patient, and the presence or absence of cardiac
involvement
 Most physicians believe that prophylaxis should continue
at least until the patient is a young adult (18 to 20 years),
which usually is 10 years from an acute attack with no
recurrence
 WHO guidelines: The World Health Organization (WHO)
published guidelines for secondary prevention of ARF in
2001
 The WHO recommendations for the duration of secondary
prophylaxis are:
 Patients without proven carditis — At least five years of
antibiotic prophylaxis following diagnosis of ARF or until
age 18
 Patients with mild mitral regurgitation — At least ten
years of prophylaxis or until age 25
 Patients with severe valve disease and/or after valve
surgery — Life-long prophylaxis
 In our opinion, individuals with documented evidence of
rheumatic heart disease should be on continuous
prophylaxis indefinitely because rheumatic fever can
recur as late as the fifth or sixth decade of life.
 Regardless of whether or not prophylaxis is continued,
there should always be a low threshold to test and treat
acute episodes of group A streptococcal pharyngitis.

Rheumatic Heart Disease

 Rheumatic heart disease is the most serious complication

of rheumatic fever.
 Acute rheumatic heart disease often produces a
pancarditis characterized by endocarditis, myocarditis,
and pericarditis.
 Endocarditis is manifested as valve insufficiency.
 The mitral valve is most commonly and the mitral valve
alone is affected in 50-60% of cases, and combined
lesions of the aortic and mitral valves occur in 20%;
Tricuspid involvement occurs only in association with
mitral or aortic disease in about 10% of cases.
 The pulmonary valve is rarely affected.
 Rheumatic mitral stenosis has a delayed onset compared
to rheumatic mitral regurgitation (MR)
 Chronic rheumatic heart disease results from single or
repeated attacks of rheumatic fever that produce rigidity
and deformity of valve cusps, fusion of the commissures,
or shortening and fusion of the chordae tendineae.
 The first clue to organic valvular disease is a murmur.
 The inflammatory process in the valve leaflets is thought
to be initiated by cross-reactivity between streptococcal
antigen and the valve tissue; there is no evidence for
active infection of the valve leaflets
 Although the incidence of rheumatic heart disease is
variable after an episode of acute rheumatic fever,
approximately 50 percent of those with evidence of
carditis develop organic valvular damage.
 In addition, up to 75 percent of patients with documented
recurrences of rheumatic fever have some form of
valvular disease after 45 years of follow-up
 Although rheumatic valve disease often results in MR in
the first two decades of life, mitral stenosis (MS) and
mixed MS/MR are more often seen in adults
 PHYSICAL EXAMINATION —
 In chronic MR, the arterial pulse may be reduced in
volume, but is usually brisk in upstroke, reflecting the
increased ejection rate and normal ejection fraction.
 Since there is a rapid reduction in the volume of forward
flow late in systole and therefore a decrease in ejection
time, the arterial pulse falls off rapidly, giving the
impression of a bounding pulse, similar to that seen with
aortic regurgitation.
 However, the pulse pressure is normal with mitral
regurgitation
 Enlargement of the left ventricle results in a leftward
displacement of the apical impulse; it is usually brisk or
hyperdynamic.
 When the mitral regurgitation is severe or when there has
been an acute exacerbation of the regurgitation as a
result of a chordal rupture, a thrill and an S3 may be
palpable.
 Signs of right-sided congestive heart failure are typically
absent unless there is associated mitral stenosis or the MR
is of long standing and is very severe
 Murmurs — The murmur of mitral regurgitation is systolic
 In most cases, the murmur is holosystolic, commencing
immediately after S1 and continuing up to and sometime
beyond and obscuring A2, a result of the persistent
pressure gradient between the left ventricle and atrium
after aortic valve closure.
 The murmur is heard best over the apex, radiating to the
axilla and when very loud may often radiate to the back.
 It is most often blowing and high pitched in quality.