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.
 Most major outbreaks occur under conditions of impoverished
overcrowding where access to antibiotics is limited.
 Rheumatic heart disease accounts for 25-50% of all cardiac admissions
internationally.
 Regions of major public health concern include the Middle East, the
Indian subcontinent, and some areas of Africa and South America.
 As many as 20 million new cases occur each year.
 The introduction of antibiotics has been associated with a rapid
worldwide decline in the incidence of ARF.
 Now, the incidence is 0.23-1.88 patients per 100,000 population
 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 incidence of an acute rheumatic episode following streptococcal
pharyngitis is 0.5-3%.
 The peak age is 6-20 years.
 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
 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
 Adequate treatment of a documented streptococcal pharyngitis
markedly reduces the incidence of subsequent rheumatic fever
 Appropriate antimicrobial prophylaxis prevents the recurrence of
disease in patients who have had ARF
 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
 Importance of pharyngitis: 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.
 The earliest and most common feature is a painful migratory arthritis,
which is present in approximately 80% of patients
 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.
Investigations

Laboratory Studies

 Group A streptococcal antigen detection tests are specific but not very
sensitive
 In contrast, antistreptococcal antibodies usually reach a peak titer (in
Todd units) at the time of onset of rheumatic fever and are more useful
 Specific antibodies to streptococcal antigens also indicate true infection
rather than mere carriage of the organism.
 Antistreptococcal antibodies include ASO, antideoxyribonuclease B
(anti-DNAse B), antistreptokinase, antihyaluronidase, and anti-DNAase
(anti-DNPase).
 These antibodies target extracellular products produced by streptococci
 ASO is found in 80-85% of patients with ARF
 The sensitivity of throat culture as evidence of recent streptococcal
infection is 25-40%
 For comparison, the sensitivity of ASO titer (adults with >240 Todd U
and children with >320 Todd U) is 80%
 The sensitivity of an elevated ASO titer in addition to anti-DNAse B or
antihyaluronidase is 90%
 Acute-phase reactants such as C-reactive protein and ESR are usually
elevated and helpful in monitoring disease activity

Imaging Studies

 Echocardiography is more sensitive than standard auscultation for

helping detect regurgitant lesions, but the prognostic significance of these
subauscultory findings is unclear
 Chest radiograph may reveal cardiomegaly
 ECG is helpful for diagnosing carditis and may reveal a prolonged PR
interval, but this finding is not necessarily associated with later cardiac
sequelae

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

 Arthritis: 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.
 When salicylates are used as therapy, the dosage should be increased
until the drug produces either a clinical effect or systemic toxicity
characterized by tinnitus, headache, or hyperpnea
 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.
 Corticosteroids should be reserved for the treatment of severe carditis
 After 2-3 weeks, the dosage may be tapered, reduced by 25% each week
 Overlap with high-dose salicylate therapy is recommended as the dosage
of the prednisone is tapered over a 2-week period to avoid poststeroid
rebound.
 In extreme cases, intravenous methylprednisolone may be used
 During this time, aspirin may be added in the dose recommended above
to achieve a serum concentration of 20 to 30mg/dL.
 Digoxin can be useful in patients with severe carditis, but its use should
be monitored closely because of the possibility of heart block
 Mild heart failure usually responds to rest and corticosteroid therapy
 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
 Sydenham chorea: We recommend corticosteroids as the initial
treatment: prednisone 1 mg/kg per day as a single dose for two weeks
and then tapered over two to three weeks.
 A repeat course may be required if an exacerbation occurs.
 Treatment with either valproic acid or carbamazepine is a reasonable
alternative, with fewer side effects.
 We reserve the use of neuroleptics, haloperidol, or pimozide for resistant
or chronic patients.
 Protracted Sydenham chorea has responded to haloperidol
 Chorea requires long-term antimicrobial prophylaxis, even if no other
manifestations of rheumatic fever evolve
 The signs and symptoms of chorea usually do not respond well to
treatment with antirheumatic agents

Antibiotic therapy

 The primary goal of treating an ARF attack is to eradicate streptococcal

organisms and bacterial antigens from the pharyngeal region
 By promptly treating streptococcal pharyngitis in susceptible hosts,
repetitive exposure to pathologically reactive antigens can be avoided.
 However, management of the current infection will probably not affect
the course of the current attack
 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 (whichever is
longer)
 Patients with mild mitral regurgitation — At least ten years of
prophylaxis or until age 25 (whichever is longer)
 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