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Rheumatic fever
1. Rheumatic fever is an inflammatory disease that occurs
following a Group A streptococcal infection, (such as
strep throat or scarlet fever). Believed to be caused by
antibody cross-reactivity that can involve the heart,
joints, skin, and brain, the illness typically develops two
to three weeks after a streptococcal infection. Acute
rheumatic fever commonly appears in children between
the ages of 5 and 15, with only 20% of first-time attacks
occurring in adults. The illness is so named because of its
similarity in presentation to rheumatism.
Pathophysiology- Rheumatic fever is a systemic disease
affecting the peri-arteriolar connective tissue and can
occur after an untreated Group A Beta hemolytic
streptococcal pharyngeal infection. It is believed to be
caused by antibody cross-reactivity. This cross-reactivity
is a Type II hypersensitivity reaction and is termed
molecular mimicry. Usually, self reactive B cells remain
anergic in the periphery without T cell co-stimulation.
During a Strep. infection, mature antigen presenting cells
such as B cells present the bacterial antigen to CD4-T
cells which differentiate into helper T2 cells. Helper T2
cells subsequently activate the B cells to become plasma
2. cells and induce the production of antibodies against the
cell wall of Streptococcus. However the antibodies may
also react against the myocardium and joints, producing
the symptoms of rheumatic fever.
Group A streptococcus pyogenes has a cell wall
composed of branched polymers which sometimes
contain M protein that are highly antigenic. The
antibodies which the immune system generates against
the M protein may cross react with cardiac myofiber
protein myosin,heart muscle glycogen and smooth
muscle cells of arteries, inducing cytokine release and
tissue destruction. However, the only proven cross
reaction is with perivascular connective tissue. This
inflammation occurs through direct attachment of
complement and Fc receptor-mediated recruitment of
neutrophils and macrophages. Characteristic Aschoff
bodies, composed of swollen eosinophilic collagen
surrounded by lymphocytes and macrophages can be
seen on light microscopy. The larger macrophages may
become Aschoff giant cells. Acute rheumatic valvular
lesions may also involve a cell-mediated immunity
3. reaction as these lesions predominantly contain T-helper
cells and macrophages.
In acute RF, these lesions can be found in any layer of the
heart and is hence called pancarditis. The inflammation
may cause a serofibrinous pericardial exudates described
as “bread-and-butter” pericarditis, which usually resolves
without sequelae. Involvement of the endocardium
typically results in fibrinoid necrosis and verrucae
formation along the lines of closure of the left-sided
heart valves. Warty projections arise from the
deposition, while subendothelial lesions may induce
irregular thickenings called MacCallum plaques.
Chronic rheumatic heart disease is characterized by
repeated inflammation with fibrinous resolution. The
cardinal anatomic changes of the valve include leaflet
thickening, commissural fusion and shortening and
thickening of the tendinous cords. Rheumatic heart
disease at autopsy with characteristic findings (thickened
mitral valve, thickened chordae tendineae,
hypertrophied left ventricular myocardium).
Etiology- Acute rheumatic fever (ARF) has been linked
definitively with a preceding streptococcal infection,
4. usually of the upper respiratory tract. Evidence is very
strong that the M protein in certain streptococci
subtypes is responsible for antigenicity.
Clinical
History- Acute rheumatic fever (ARF) is associated with 2
distinct patterns of presentation.
The first pattern of presentation is sudden onset. It
typically begins as polyarthritis 2-6 weeks after
streptococcal pharyngitis and is usually characterized
by fever and toxicity.
If the initial abnormality is mild carditis, ARF may be
insidious or subclinical.
Age at onset influences the order of complications.
Younger children tend to develop carditis first, whereas
older patients tend to develop arthritis first.
Physical-Modified Jones criteria were first published in
1944 by T. Duckett Jones, MD.They have been
periodically revised by the American Heart Association in
collaboration with other groups. According to revised
Jones criteria, the diagnosis of rheumatic fever can be
made when two of the major criteria, or one major
5. criterion plus two minor criteria, are present along with
evidence of streptococcal infection. Exceptions are
chorea and indolent carditis, each of which by itself can
indicate rheumatic fever.
Major criteria
Migratory polyarthritis: a temporary migrating
inflammation of the large joints, usually starting in
the legs and migrating upwards.
Carditis: inflammation of the heart muscle which can
manifest as congestive heart failure with shortness
of breath, pericarditis with a rub, or a new heart
murmur.
Subcutaneous nodules: painless, firm collections of
collagen fibers over bones or tendons. They
commonly appear on the back of the wrist, the
outside elbow, and the front of the knees.
Erythema marginatum: a long lasting rash that
begins on the trunk or arms as macules and spreads
outward to form a snake like ring while clearing in
the middle. This rash never starts on the face and it
is made worse with heat.
6. Sydenham's chorea (St. Vitus' dance): a
characteristic series of rapid movements without
purpose of the face and arms. This can occur very
late in the disease.
Minor criteria
Fever
Arthralgia: Joint pain without swelling
Raised Erythrocyte sedimentation rate or C reactive
protein
Leukocytosis
ECG showing features of heart block, such as a
prolonged PR interval
Supporting evidence of Streptococcal infection:
elevated or rising Antistreptolysin O titre or DNAase.
Previous episode of rheumatic fever or inactive heart
disease
Other signs and symptomsAbdominal pain
Nose bleeds
Differential Diagnoses-
7. - Aortic Regurgitation
-Pediatrics, Scarlet Fever
- Atrial Fibrillation
-Acute
Pericarditis
- Endocarditis
- Reactive Arthritis
Huntington Chorea
- Rheumatoid Arthritis
- Lyme Disease
-Scarlet Fever
- Mitral Regurgitation
- Systemic Lupus
Erythematosus
Mitral Stenosis
- Myocarditis
-Pediatrics, Kawasaki Diseas
- Leukemia
-Juvenile rheumatoid
arthritis
DiagnosisLaboratory Studies
- No specific confirmatory laboratory tests exist for
acute rheumatic fever. However, several laboratory
findings indicate continuing rheumatic inflammation.
Some are part of the Jones minor criteria.
- Streptococcal antibody tests disclose preceding
streptococcal infection.
8. - The CDC has stated that a rapid antigen test in the
appropriate clinical setting is sufficient to make the
diagnosis of active GABHS infection and begin
treatment.
- Isolate group A streptococci via throat culture. A
significant percentage will result in a culture positive
for group A beta-hemolytic Streptococcus (GABHS).
However, a culture positive for GABHS does not
definitively prove active infection. Some patients are
carriers.
- Acute-phase reactants (eg, erythrocyte
sedimentation rate [ESR], C-reactive protein [CRP] in
serum and leukocytosis) may show an increase in
serum complement, mucoproteins, alpha-2, and
gamma globulins. Anemia is usually caused by
suppression of erythropoiesis.
- PR-interval prolongation is present in approximately
25% of all cases and is neither specific for nor
diagnostic of acute rheumatic fever.
- Although there are a few small studies that show the
contrary, troponins have not been shown to be
helpful in making the diagnosis because ischemia
and necrosis are not the major cardiac problems.
9. - Synovial fluid analysis may demonstrate an elevated
white blood cell count with no crystals or organisms.
- Differences exist among nations in terms of
diagnosing and treating GABHS pharyngitis. Most
North American, French, and Finnish guidelines
consider diagnosis of streptococcal infection
essential (with either rapid antigen detection or with
formal culture) and advise antibiotic therapy when
streptococci is detected. Several European
guidelines consider streptococcal infection a selflimited disease and do not recommend antibiotics.
Imaging Studies
- Echocardiography may be helpful in establishing
carditis. Some suggest it be performed in all
suspected cases.
- Chest radiography should be performed to
determine presence of cardiomegaly and congestive
heart failure.
Treatment- The goals of treatment for rheumatic fever
are to destroy any remaining group A streptococcal
10. bacteria, relieve symptoms, control inflammation and
prevent recurring episodes of rheumatic fever.
Antimicrobials- Because of the direct link between ARF
and group A beta-streptococcal infection, the first step in
treatment is the eradication of the organism.
-Penicillin G benzathine (Bicillin LA, Bicillin C-R)Interferes with synthesis of cell wall mucopeptide during
active multiplication, resulting in bactericidal activity
against susceptible bacteria. Adult- 2.4 million U IM once
-Penicillin G procaine (Crysticillin, Wycillin)- Long-acting
parenteral penicillin (IM only) indicated in the treatment
of moderately severe infections caused by penicillin G–
sensitive microorganisms.Some prefer 10-d therapy.
Administer by deep IM injection only into the upper
outer quadrant of the buttock. In infants and small
children, the midlateral aspect of the thigh may be the
best site for administration. Adult- 2.4 million U IM once.
- Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK,
Veetids), Amoxicillin- Inhibits the biosynthesis of the cellwall mucopeptide and is effective during the stage of
active multiplication. Inadequate concentrations may
11. produce only bacteriostatic effects. Penicillin VK is the
oral alternative for the treatment of rheumatic fever.
Some authors suggest that once-daily amoxicillin is as
effective and can be recommended as an alternative
because compliance is likely to be better. Adult- 500 mg
PO q6h for 10 d
- Erythromycin (EES, E-Mycin, Ery-Tab, Erythrocin)DOC(drug of choice) for patients allergic to penicillin;
inhibits RNA-dependent protein synthesis, possibly by
stimulating the dissociation of peptidyl tRNA from
ribosomes, which inhibits bacterial growth.
In children, age, weight, and 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
doubled. Adult- 1 g/d PO divided bid for 10 d
-Azithromycin (Zithromax)- Acts by binding to 50S
ribosomal subunit of susceptible microorganisms and
blocks dissociation of peptidyl tRNA from ribosomes,
causing RNA-dependent protein synthesis to arrest.
12. Treats mild-to-moderate microbial infections. Adult- 500
mg on day 1 followed by 250 mg/d for 4 additional days.
Glucocorticoids- These agents possess antiinflammatory (ie, glucocorticoid) and salt-retaining (ie,
mineralocorticoid) properties. Glucocorticoids cause
profound and varied metabolic effects. In addition, these
agents modify the body's immune response to diverse
stimuli.
Prednisone (Deltasone, Sterapred)- Patients with carditis
require prednisone instead of aspirin. The goal is to
decrease myocardial inflammation. Some authors
suggest that carditis without associated cardiomegaly or
congestive heart failure be treated with aspirin instead of
glucocorticoids.
Glucocorticoids are useful in treatment of inflammatory
and autoimmune disorders. Adult- 60-80 mg/d PO
Neuroleptic agents- These agents may help to control
the chorea associated with ARF.
Haloperidol (Haldol)- A dopamine receptor blocker useful
in the treatment of irregular spasmodic movements of
13. limbs or facial muscles.
0.5-2 mg PO bid/tid
Adult-
Inotropic agents- Some believe that digoxin may be
helpful in congestive heart failure.
Digoxin (Lanoxin)- Cardiac glycoside with direct inotropic
effects and indirect effects on the cardiovascular system.
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- 0.125-0.375 mg PO qd
Anti-inflammatory agents- Reduce the inflammation
associated with the disease process. Joints and heart are
the targets of inflammation, but carditis is treated with
glucocorticoids as noted above.
Aspirin - Treats mild to moderate pain. Inhibits
prostaglandin synthesis, which prevents formation of
platelet-aggregating thromboxane A2.
Adult- 6-8 g/d PO for 2 mo or until ESR has returned to
normal
14. Naproxen (Anaprox, Naprelan, Naprosyn)- For relief of
mild to moderate pain; inhibits inflammatory reactions
and pain by decreasing activity of cyclooxygenase, which
is responsible for prostaglandin synthesis.
NSAIDs decrease intraglomerular pressure and decrease
proteinuria. Adult- 250-500 mg PO bid; may increase to
1.5 g/d for limited periods.
Complications-
Carditis
Mitral stenosis
Mitral regurgitation
Aortic stenosis
Congestive heart failure (CHF)