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Abdullah Afif Siregar
Departemen Kardiologi dan Kedokteran
Fakultas Kedokteran USU

Rheumatic fever is an immunologically

mediated inflammatory disease, that
occurs as a delayed sequel to group A
streptococcal throat infection, in
genetically susceptible individuals.
Rheumatic heart disease is the most
serious complication of rheumatic fever
Acute rheumatic fever and rheumatic heart
disease are thought to result from an
autoimmune response, but the exact
pathogenesis remains unclear

The rheumatic fever follows 0.3% of cases of group A

beta-hemolytic streptococcal pharyngitis in children.
As many as 39% of patients with acute rheumatic fever
may develop varying degrees of pancarditis with
associated valve insufficiency, heart failure, pericarditis,
and even death.
With chronic rheumatic heart disease, patients develop
valve stenosis with varying degrees of regurgitation,
atrial dilation, arrhythmias, and ventricular dysfunction.
Chronic rheumatic heart disease remains the leading
cause of mitral valve stenosis and valve replacement in
adults and children

Rheumatic fever develops in children and adolescents following
pharyngitis with group A beta-hemolytic Streptococcus (ie,
Streptococcus pyogenes).
The organisms attach to the epithelial cells of the upper
respiratory tract and produce a battery of enzymes allowing them
to damage and invade human tissues.
After an incubation period of 2-4 days, the invading organisms
elicit an acute inflammatory response with 3-5 days of sore throat,

fever, malaise, headache, and an elevated leukocyte count.

In 0.3-3% of cases, infection leads to rheumatic fever several
weeks after the sore throat has resolved. Only infections of the
pharynx initiate or reactivate rheumatic fever.
The organism spreads by direct contact with oral or respiratory
secretions, and spread is enhanced by crowded living conditions.

Etiopathogenesis :
The pathogenic mechanisms involved in the development of RF remain

unclear. But it is evident that an abnormal humoral and cellular immune

response occurs.
Antigenic mimicry between streptococcal antigens, mainly M-protein
epitopes and human tissues, such as heart valves, myosin and
tropomyosin, brain proteins, synovial tissue and cartilage has been
proposed as the triggering factor leading to autoimmunity in individuals
with genetic predisposition.
Several genetic markers of susceptibility have been studied but no
consistent association found. Associations with different HLA class II
antigens have been observed in several populations.
Molecular mimicry was first demonstrated by humoral immune response.
Streptococcal antibodies cross-react with several human tissues including
heart, skin, brain, glomerular basement membrane, striated and smooth
The presence of CD4+ T cells at lesions sites in the heart has been
demonstrated, suggesting a direct role of these cells in the pathogenesis of

Etiopathogenesis :

Infiltrating T lymphocytes from

heart lesions of severe RHD

patients and peripheral T
lymphocytes were capable of
recognising immunodominant
myocardium M5 peptides and
valve proteins. These results
showed the significance of
molecular mimicry between
beta hemolytic streptococci and
heart tissue assessing the T-cell
repertoire leading to local tissue
damage in RHD.
Figure 1: Schematic representation
of the aetiopathogenic events
occurring during the development
of carditis


Sambungan Tabel 4.1

Carditis (40% )

Carditis (40% )

Clinical picture of carditis :

The clinical picture includes high pulse rate, congestive
heart failure, arrhytmias and pericardial friction rubs.
On the first attack, valvulitis is suspected in the presence
of a new apical systolic murmur of mitral regurgitation
(associated or not with an apical mid-diastolic murmur)
and/or a basal diastolic murmur of aortic regurgitation.
Cardiomegaly is noted on X-Ray and on echocardiogram.
Myocarditis and/or pericarditis in the absence of valvular
involvement is unlikely due to acute RF

Polyarthritis (75%)
Arthritis is the most common manifestation,
present in 60-80% of patients.
It usually affects the peripheral large joints;
small joints and axial skeleton are rarely
Knees, ankles, elbows and wrists are the
frequently affected. The joints are red, warm
and swollen.
Arthritis is characteristically asymmetrical,
migratory, and very painful, although some
patients may present mild joint complaints. It
usually resolves spontaneously at the most in
2 or 3 weeks.
Arthritis in ARF has an excellent response to

Chorea :

Sydenhams chorea is
characterized by involuntary
movements, specially of the
face and limbs, muscle
weakness, disturbances of
speech and gait.
Children usually exhibit
concomitant psychologic
dysfunction, especially
disorder, increased emotional
lability, hyperactivity,
irritablility and age-regressed
It is usually a delayed
manifestation, and is often
the sole manifestation of ARF.

Erythema marginatum :
This is an evanescent, erythematous, non-pruritic
rash with pale centers and rounded or serpiginous
margins. Lesions occur mainly on the trunk and
proximal extremities and may be induced by
application of heat


Based on Jones Criteria, 1992 Update

- 2 Major criteria + 1 Minor criteria, or
- 1 Major criteria + 2 minor criteria

* plus supporting evidence of preceding GAS


Table : Differential diagnosis of rheumatic fever

Juvenile rheumatoid arthritis

Systemic lupus erythematosus

Infective endocarditis

Reactive arthritis

Sickle cell disease

Drug reactions

Other connective tissue




Gonoccocal arthritis


Lyme disease

Serum sickness

Treatment :
Medical therapy involves the following 5 areas:
1. Treat group A streptococcal infection regardless of organism
2. Steroids and salicylates are useful in the control of pain and
inflammation. The nonsteroidal anti-inflammatory drug (NSAID)
naproxen has also been studied. It is effective and may be easier
to use than aspirin.
3. Heart failure may require digitalis.
4. Administer prophylaxis to patients who have developed ARF.
Patients with ARF should receive prophylaxis against future
GABHS infections. Available regimens include benzathine
penicillin G 1.2 million U IM every month, penicillin V 200,000 U
or 250 mg PO bid, or erythromycin 250 mg PO bid. Most
authorities suggest that prophylaxis be given for 5 years. For
those who have rheumatic carditis, some authorities suggest lifelong prophylaxis.
5. Haloperidol may be helpful in controlling chorea.

Drug Name

Penicillin G benzathine
(Bicillin LA)

Penicillin G procaine
(Crysticillin, Wycillin)

Penicillin VK (Beepen-VK,
Betapen-VK, Robicillin VK,


Interferes with synthesis of

cell wall mucopeptide
during active multiplication
resulting in bactericidal
activity against susceptible
Because of its prolonged
blood level, several
authors believe this to be
the DOC. Others prefer
daily injections.

Long-acting parenteral
penicillin (IM only) indicated
in the treatment of
moderately severe
infections caused by
penicillin G-sensitive
Some prefer 10-d therapy.
Administer by deep IM
injection only into the upper
outer quadrant of the

Inhibits the biosynthesis of the

cell-wall mucopeptide and is
effective during the stage of
active multiplication.
Inadequate concentrations
may produce only
bacteriostatic effects. Penicillin
VK is the oral alternative for
the treatment of rheumatic

Adult Dose

2.4 million U IM once

2.4 million U IM once

500 mg PO q6h for 10 d

Pediatric Dose

Infants and children <30

lb: 600,000 U IM once
Children 30-60 lb: 900,000
to 1.2 million U IM once

Infants and children <30 lb:

600,000 U IM
Children 30-60 lb: 900,000
to 1.2 million U IM

<12 years: 25-50 mg/kg/d PO

divided tid/qid; not to exceed 3
g/d >12 years: Administer as
in adults




Documented hypersensitivity


Probenecid can increase

penicillin effectiveness by
decreasing its clearance;
coadministration of
tetracyclines can decrease
penicillin effectiveness

Increases risk of bleeding

when administered
concurrently with warfarin;
ethacrynic acid, aspirin,
indomethacin, and
furosemide may compete
with penicillin G for renal
tubular secretion increasing
penicillin serum

Probenecid may increase

effectiveness by decreasing
clearance; tetracyclines are
bacteriostatic, causing a
decrease in the effectiveness
of penicillins when

B - Usually safe but benefits

B - Usually safe but benefits


B - Usually safe but

administered concurrently

Drug Name

Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin)


DOC for patients allergic to penicillin; inhibits RNAdependent protein synthesis, possibly by stimulating the
dissociation of peptidyl t-RNA from ribosomes, which
inhibits bacterial growth.
In children, age, weight, and the severity of infection
determine the proper dosage. When bid dosing is
desired, one-half the daily dose may be administered
q12h. For more severe infections, the dose may be

Adult Dose

1 g/d PO divided bid for 10 d


30-50 mg/kg/d PO divided bid


Documented hypersensitivity; hepatic impairment


Coadministration may increase toxicity of theophylline,

digoxin, carbamazepine, and cyclosporine; may
potentiate anticoagulant effects of warfarin;
coadministration with lovastatin and simvastatin,
increases risk of rhabdomyolysis


B - Usually safe but benefits must outweigh the risks.


Caution in liver disease; estolate formulation may cause

cholestatic jaundice; GI adverse effects are common
(give doses pc); discontinue use if nausea, vomiting,

Drug Category: Glucocorticoids

Drug Name

Prednisone (Deltasone, Sterapred)


Patients with carditis require prednisone instead of aspirin. The

goal is to decrease myocardial inflammation.
Useful in treatment of inflammatory and autoimmune disorders.
Reversing increased capillary permeability and suppressing PMN
activity may decrease inflammation.

Adult Dose

60-80 mg/d PO

Pediatric Dose

2 mg/kg/d PO


Documented hypersensitivity; viral, fungal, or tubercular skin



Coadministration with estrogens may decrease clearance;

concurrent use with digoxin, may cause digitalis toxicity
secondary to hypokalemia; phenobarbital, phenytoin, and
rifampin may increase metabolism of glucocorticoids (consider
increasing maintenance dose); monitor for hypokalemia with
coadministration of diuretics



B - Usually safe but benefits must outweigh the risks.

Abrupt discontinuation of glucocorticoids may cause adrenal
crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic
ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis,
myasthenia gravis, growth suppression, and infections may occur
with glucocorticoid use

Anti inflammatory.
Drug Name

Aspirin (Ascriptin, Bayer Buffered Aspirin, Ecotrin)


Treats mild to moderate pain. Inhibits prostaglandin synthesis, which

prevents formation of platelet-aggregating thromboxane A2.

Adult Dose

6-8 g/d PO for 2 mo or until ESR has returned to normal

Pediatric Dose

80-100 mg/kg/d PO for 2 mo or until ESR has returned to normal


Documented hypersensitivity; liver damage, hypoprothrombinemia,

vitamin K deficiency, bleeding disorders, asthma; because of
association with Reye syndrome, do not use in children ( <16 y) with


Effects may decrease with antacids and urinary alkalinizers;

corticosteroids decrease salicylate serum levels; additive
hypoprothrombinemic effects and increased bleeding time may
occur with coadministration of anticoagulants; may antagonize
uricosuric effects of probenecid and increase toxicity of phenytoin
and valproic acid; doses > 2 g/d may potentiate glucose lowering
effect of sulfonylurea drugs


C - Safety for use during pregnancy has not been established.


Pregnancy category D if full dose given during third trimester; may

cause transient decrease in renal function and aggravate chronic
kidney disease; avoid use in patients with severe anemia, with
history of blood coagulation defects, or taking anticoagulants

Drug Category: Neuroleptic agents

May help to control the chorea associated with ARF.
Drug Name

Haloperidol (Haldol)


A dopamine receptor blocker useful in the treatment of irregular

spasmodic movements of limbs or facial muscles.

Adult Dose

0.5-2 mg PO bid/tid

Pediatric Dose

<3 years: Not established

3-12 years: 0.05 mg/kg/d or 0.25-0.5 mg/d bid/tid; increase by 0.25-0.5
mg q5-7d
Maintenance dose: 0.05-0.15 mg/kg/d bid/tid; not to exceed 0.15 mg/kg/d
>12 years: Administer as in adults


Documented hypersensitivity; narrow-angle glaucoma; bone marrow

suppression; severe cardiac and liver disease; severe hypotension;
subcortical brain damage


May increase tricyclic antidepressant serum-concentrations and

hypotensive action of antihypertensive agents; phenobarbital or
carbamazepine may decrease effects; coadministration with
anticholinergics may increase intraocular pressure; encephalopathy-like
syndrome associated with concurrent administration of lithium and



C - Safety for use during pregnancy has not been established.

Severe neurotoxicity manifesting as rigidity, or inability to walk or talk
may occur in patients with thyrotoxicosis also receiving antipsychotics; if
IV/IM, watch for hypotension; caution in CNS depression or cardiac

Drug Category: Inotropic agents

Some believe that digoxin may be helpful in congestive heart failure.
Drug Name

Digoxin (Lanoxin)


Cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular
Effects on the myocardium involve a direct action on cardiac muscle that increases
myocardial systolic contractions and indirect actions that result in increased carotid sinus
nerve activity and enhanced sympathetic withdrawal for any given increase in mean
arterial pressure.

Adult Dose

0.125-0.375 mg PO qd

Pediatric Dose

Digitalizing dose:
2-5 years: 30-40 mcg/kg PO
5-10 years: 20-35 mcg/kg PO
>10 years: 10-15 mcg/kg PO
Maintenance dose: 25-35% of PO loading dose


Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic

stenosis; constrictive pericarditis; carotid sinus syndrome


Medications that may increase digoxin levels include alprazolam, benzodiazepines,

bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem,
aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin,
felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine,
ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications
that may decrease serum digoxin levels include aminoglutethimide, anti histamines,
cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol,
hydantoins,hypo glycemic agents, antineoplastic treatment combinations (including
carmustine, bleomycin, methotre xate, cytarabine, doxorubicin, cyclophosphamide,
vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate,
sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid


C - Safety for use during pregnancy has not been established.

Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce
arrhythmias ; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia

Table : Secondary prevention of rheumatic fever.


Therapeutic Scheme

penicillin G

1,200,000 U every 4 weeks*, IM


Penicillin V

250mg twice daily, PO



500mg once daily for patients < 27kg; 1g once

daily for patients > 27kg, PO

For individuals allergic to penicillin and sulfadiazine:


250mg twice daily, PO

*In high-risk situations, administration every 3 weeks is recommended.

Table. Guidelines for Bed Rest and

Ambulation and Recommended
antiinflammatory agents

Bed Rest

1-2 wk


2-3 wk


4-6 wk


2-4 mo

Indoor ambulation

1-2 wk

2-3 wk

4-6 wk

2-3 mo

Outdor activity

1-2 wk

2-3 wk

4-6 wk

2-3 mo

Full activity

1-2 wk

2-3 wk

4-6 wk

2-3 mo




2-4 wk
2-4 wk

2-6 wk
2-6 wk

Minimal Carditis Questionable cardiomegaly ; Moderate carditis definite but mild

cardiomegaly, Severe carditis, marked cardiomegaly or CHF

Mitral stenosis
Congestive heart failure (CHF)

Sequelae are limited to the heart and are
dependent upon the severity of the carditis
during the acute attack.

Rheumatic Heart

Rheumatic heart disease is the most serious

complication of rheumatic fever.
Acute rheumatic fever follows 0.3% of cases of
group A beta-hemolytic streptococcal pharyngitis
in children. As many as 39% of patients with acute
rheumatic fever may develop varying degrees of
pancarditis with associated valve insufficiency,
heart failure, pericarditis, and even death.
With chronic rheumatic heart disease, patients
develop valve stenosis with varying degrees of
regurgitation, atrial dilation, arrhythmias, and
ventricular dysfunction. Chronic rheumatic heart
disease remains the leading cause of mitral valve
stenosis and valve replacement in adults

In the US:
Prevalence of rheumatic heart disease in the United States now is less than
0.05 per 1000 population
The incidence of rheumatic fever and rheumatic heart disease has not
decreased in developing countries. Retrospective studies reveal developing
countries to have the highest figures for cardiac involvement and recurrence
rates of rheumatic fever. Estimations worldwide are that 5-30 million children
and young adults have chronic rheumatic heart disease, and 90,000 patients
die from this disease each year. There were no data available in Indonesia

Rheumatic heart disease is the major cause of morbidity from
rheumatic fever and the major cause of mitral insufficiency and
stenosis in the Indonesia and the world.
Variables that correlate with severity of valve disease include the
number of previous attacks of rheumatic fever, the length of time
between the onset of disease and start of therapy, and sex. (The
disease is more severe in females than in males.) Insufficiency from
acute rheumatic valve disease resolves in 60-80% of patients who
adhere to antibiotic prophylaxis.

The race (when controlled for socioeconomic variables) has not been
documented to influence disease incidence.

Rheumatic fever occurs in equal numbers in males and females, but
the prognosis is worse for females than for males.

Rheumatic fever is principally a disease of childhood,
with a median age of 10 years, although it also occurs in
adults (20% of cases).
Socio-economic factors :
It is well known that socioeconomic and environmental
factors play an indirect, but important, role in the magnitude
and severity of RF and RHD. Such factor as a shortage of
resources for providing quality health care, inadequate
expertise of health-care providers, and a low level of
awareness of the disease in the community can all impact
the expression of the disease in populations. Crowding
adversely affects rheumatic fever incidence

Cardiac manifestations of chronic rheumatic heart disease :

Valve deformities,
cardiac hemolytic anemia, and
atrial arrhythmias
are the most common cardiac manifestations of chronic
rheumatic heart disease.
Valve deformities
Mitral stenosis Mitral regurgitasi occurs in 25% of patients
with chronic rheumatic heart disease and in association with
mitral insufficiency in another 40%.
Aortic regurgitasi Aortic stenosis are typically from chronic
rheumatic heart disease. The valve commissures and cusps
become adherent and fused, and the valve orifice becomes small
with a round or triangular shape.

Thromboembolism occurs as a complication of mitral

stenosis. It is more likely to occur when the left atrium
is dilated, cardiac output is decreased, and the
patient is in atrial fibrillation.
Cardiac hemolytic anemia is related to disruption of
the red blood cells by a deformed valve. Increased
destruction and replacement of platelets also may
Atrial arrhythmias typically are related to a chronically
enlarged left atrium (from a mitral valve abnormality).
Successful cardioversion of atrial fibrillation to sinus
rhythm is more likely to be successful if the left atrium
is not markedly enlarged, the mitral stenosis is mild,
and the patient has been in atrial fibrillation for less
than 6 months.





Medical Care:
Medical therapy is directed toward eliminating
the group A strepto coccal pharyngitis
Treatment of the acute inflammatory
manifestations of acute rheumatic fever consists
of administering salicylates and steroids.
If moderate-to-severe carditis is indicated by
cardiomegaly, congestive heart failure, or thirddegree heart block, oral prednisone should be
added to salicylate therapy.
Preventive and prophylactic therapy is indicated
after rheumatic fever and rheumatic heart
disease to prevent further damage to valves.


Surgical Care:
When heart failure persists or worsens after
aggressive medical therapy for acute rheumatic
heart disease, surgery to decrease valve
insufficiency may be life-saving.
Forty percent of patients with acute rheumatic fever
subsequently develop mitral stenosis as adults.
In patients with critical stenosis, mitral valvulotomy,
percutaneous balloon valvuloplasty, or mitral valve
replacement may be indicated.
Due to high rates of recurrent symptoms after
annuloplasty or other repair procedures, valve
replacement appears to be the preferred surgical

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