RHEUMATIC FEVER AND

RHEUMATIC HEART DISEASE

PATHOGENESIS
MORPHOLOGY
CLINICAL FEATURES
LAB DIAGNOSIS
Rheumatic Fever
• Epidemiology

• ~3% of persons with untreated group A streptococcal

pharyngitis develop rheumatic fever

• 15-20 million new cases a year in developing countries

• Risk factors
– Low standard of living
– Crowding
INTRODUCTION
• Rheumatic fever (RF) is an acute, immunologically mediated,
multisystem inflammatory disease classically occurring a few weeks
after group A streptococcal pharyngitis
• RHD is characterized principally by deforming fibrotic valvular disease,
particularly involving the mitral valve
• RHD is virtually the only cause of mitral stenosis.
• The incidence and mortality rate of RF and RHD have declined
remarkably in many parts of the world over the past century
• Reasons include improved sanitation, and rapid diagnosis and
treatment of streptococcal pharyngitis.
• Group A streptococcus pyogenes has a cell wall
composed of branched polymers which sometimes
contain "M proteins " that are highly antigenic

• The antibodies which the immune system generates

against the "M proteins" may cross react with cardiac
myofiber protein myosin and smooth muscle cells of
arteries, inducing cytokine release and tissue
destruction

• This inflammation occurs through direct attachment

of complement and Fc receptor-mediated
recruitment of neutrophils and macrophages
PATHOGENESIS
• Acute rheumatic fever results from host immune responses to group
A streptococcal antigens that cross-react with host proteins.
• Antibodies and CD4+ T cells directed against streptococcal M
proteins can also in some cases recognize cardiac self antigens.
• Antibody binding can activate complement, as well as recruit Fc
receptor– bearing cells (neutrophils and macrophages)
• Cytokine production by the stimulated T cells leads to macrophage
activation (e.g., within Aschoff bodies).
• Damage to heart tissue may thus be caused by a combination of
antibody- and T cell–mediated reactions
• Cytokine production by the stimulated T cells leads to macrophage
activation
• Damage to heart tissue may thus be caused by a combination of
antibody- and T cell–mediated reactions
• Only a small minority of infected patients develop rheumatic fever
(estimated at 3%)
• A genetic susceptibility is likely to influence the development of the
cross-reactive immune responses.
• The chronic fibrotic lesions are the consequence of healing and
scarring associated with the resolution of the acute inflammation.
• Inflammation of the endocardium and the left-sided valves typically
results in fibrinoid necrosis within the cusps or tendinous cords.
• Overlying these necrotic foci and along the lines of closure are small
(1 to 2 mm) vegetations, called verrucae.
• RHD is one of the forms of vegetative valve disease, each of which
exhibit their own characteristic morphologic features
• Subendocardial lesions, perhaps exacerbated by regurgitant jets, can
induce irregular thickenings called MacCallum plaques, usually in the
left atrium.
• McCallum’s patch is an irregular, wrinkled map-like thickening of the
mural endocardium located on the posterior wall of the left atrium.

• It is formed due to endocardial and subendocardial damage induced

by regurgitation of blood through the mitral valve.

• Involvement of the myocardium is called myocarditis and it can result

in dilatation of the chamber.
MORPHOLOGY

• During acute RF, focal inflammatory lesions are found in various tissues.
• Distinctive lesions in the heart—called Aschoff bodies—are composed of
foci of T lymphocytes, occasional plasma cells, and plump activated
macrophages called Anitschkow cells.
• Macrophages have abundant cytoplasm and central round to ovoid nuclei
(occasionally binucleate)
• Chromatin condenses into a central, slender, wavy ribbon ( “caterpillar
cells”).
• During acute RF, diffuse inflammation and Aschoff bodies may be found in
any of the three layers of the heart, resulting in pericarditis, myocarditis, or
endocarditis (pancarditis).
• Acute rheumatic fever can involve all the layers of the heart (acute
rheumatic pancarditis).
• Involvement of the endocardium is called endocarditis and can be of
two types – valvular or mural.
• Valvular endocarditis predominantly involves the left sided valves
ie. mitral and aortic with deposition of fibrin along the lines of the
closure or along the chordae tendinae.
• These deposits all organized to form warty vegetations called
verrucae which are firmly attached to the valve at the line of closure.
• The cardinal anatomic changes of the mitral valve in chronic RHD are
a. Leaflet thickening
b. Commissural fusion and shortening, and
c. Thickening and fusion of the tendinous cords
• The mitral valve is virtually always involved in chronic RHD
• It is affected in isolation in roughly two-thirds of cases, and along with
the aortic valve in another 25%.
• Tricuspid valve involvement is infrequent, and the pulmonary valve
is only rarely affected.
• In rheumatic mitral stenosis, calcification and fibrous bridging across
the valvular commissures create “fish mouth” stenoses
• With tight mitral stenosis, the left atrium progressively dilates and
may harbor mural thrombi that can embolize.
• Long-standing congestive changes in the lungs may induce pulmonary
vascular and parenchymal changes; over time, these can lead to right
ventricular hypertrophy
• The left ventricle is largely unaffected by isolated pure mitral stenosis.
• Microscopically, valves show organization of the acute inflammation,
with post-inflammatory neovascularization and transmural fibrosis
that obliterate the leaflet architecture.
• Aschoff bodies are rarely seen in surgical specimens or autopsy tissue
from patients with chronic RHD, because of the long intervals
between the initial insult and the development of the chronic
deformity.
CLINICAL FEATURES
• Acute RF typically appears 10 days to 6 weeks after a group A streptococcal
infection in about 3% of patients.
• It occurs most often in children between ages 5 and 15, but first attacks can
occur in middle to later life.
• Pharyngeal cultures for streptococci are negative by the time the illness begins
• Antibodies to one or more streptococcal enzymes, such as streptolysin O and
DNase B, can be detected in the sera of most patients with RF.
• The predominant clinical manifestations are carditis and arthritis, the latter more
common in adults than in children.
Clinical Features

RF is characterized by a constellation of major manifestations:

• Migratory polyarthritis of the large joints
• Pancarditis (myocarditis, pericarditis, or endocarditis)
• Subcutaneous nodules (typically on extensor surfaces of extremities)
• Erythema marginatum, an irregular circinate skin rash
• Sydenham chorea, a neurologic disorder with involuntary rapid
movements
• The diagnosis of acute rheumatic fever is made by using the Jones criteria.
• At least two of the major criteria or one major and 2 minor criteria need to
be present in order to make the diagnosis. It is also necessary to
demonstrate a preceding group A streptococcal infection.
• The major criteria can be easily remembered by using the
mnemonic CANCER
C – carditis
A – arthritis
N – nodules (subcutaneous)
C – Chorea
ER – Erythema marginatum
• Arthritis typically begins with migratory polyarthritis (accompanied by
fever) in which one large joint after another becomes painful and
swollen for a period of days and then subsides spontaneously, leaving
no residual disability.
• Clinical features related to acute carditis include pericardial friction
rubs, tachycardia, and arrhythmias.
• Myocarditis can cause cardiac dilation that may culminate in
functional mitral valve insufficiency or even heart failure.
• Approximately 1% of affected individuals die of fulminant RF
involvement of the heart.
Skin (Erythema Marginatum)
• Skin lesions: The classical erythema marginatum—
lesions with prominent margins slightly raised
 Central nervous system (chorea)
Sydenham's chorea
• Occurs in children, rare in adults
• The choreiform movements affect
particularly the head and the upper
limbs
• They may be generalized or restricted
to one side of the body (hemi-chorea)
• Chorea eventually resolves
completely, usually within 6 weeks
• likely due to molecular mimicry, with
autoantibodies reacting with brain
ganglioside
Subcutaneous nodules
• Subcutaneous nodules : These are
painless, round, firm lumps overlaid
by normal looking skin

• They range from a few millimeters to

1.5 cm in diameter, and are localized
over bony prominences like the elbow,
shin and spine. They sometimes last
longer than a month
Investigation of Rheumatic Fever
• Anti-streptolysin O (ASO) titer
• At least 80% of patients with ARF have an elevated anti-
streptolysin O titer at presentation
• Rising titer is more convincing

• Anti-DNAse B
• Anti-hyaluronidase test

• Throat culture for group A streptococci (obtain 2 or 3

cultures)
Rheumatic Fever – Clinical Course
• Subsequent attacks
• Increased vulnerability to reactivation of disease with subsequent strep
infections
• Same symptoms with each attack
• Carditis worsens with each attack
• Heart valves are frequently deformed (mitral)
• Heart failure develops after decades
• After an initial attack there is increased vulnerability to reactivation of
the disease with subsequent pharyngeal infections
• Same manifestations are likely to appear with each recurrent attack.
Damage to the valves is cumulative.
• Turbulence induced by ongoing valvular deformities leads to
additional fibrosis.
• Clinical manifestations appear years or even decades after the initial
episode of RF and depend on which cardiac valves are involved.
LAB DIAGNOSIS
• There's no definitive diagnostic test for acute rheumatic fever.
• A clinical diagnosis of acute rheumatic fever should be made using
the 2015 revised Jones Criteria.
• The Jones Criteria can be used to diagnose initial as well as recurrent
illnesses.
Criteria

• The presence of the following indicates a high probability of an initial acute

rheumatic fever illness in any risk population:
• 2 major manifestations
• 1 major and 2 minor manifestations
• More than 1 joint manifestation: Classify them as either one major or one
minor criteria, not both. For example, if there's evidence of arthritis (a
major criteria), then arthralgia doesn't count as a minor criteria.
• More than 1 cardiac manifestation: Classify them as either one major or
one minor criteria, not both. For example, if there's evidence of carditis (a
major criteria), then a prolonged PR interval doesn't count as a minor
criteria.
Preceding infection

• In most cases, there should also be evidence of preceding group A

streptococcal infection. Evidence to support an antecedent group A
strep infection include:
• Positive throat culture or rapid streptococcal antigen test
• Elevated or rising streptococcal antibody titer
COMPLICATIONS
• Cardiac hypertrophy and dilation, and heart failure
• Individuals with chronic RHD may suffer from arrhythmias
(particularly atrial fibrillation in the setting of mitral stenosis),
thromboembolic complications, and infective endocarditis
• The long-term prognosis is highly variable.
• Surgical repair or prosthetic replacement of diseased valves has
greatly improved the outlook for persons with RHD.
Take home message
• Rheumatic heart disease results from cross reacting
antibodies binding the heart valves
• Repeated attacks of Streptococcal throat infection
over the years damage heart valves resulting in either
stenotic or incompetent heart valves
• Treatment involves surgical replacement of the
damaged heart valves
• In patients with rheumatic fever long term
administration of penicillin is recommended for
prevention of future infections by group A
Streptococcus
CHART- 15

• A nine-year-old girl complains of pain and swelling of the knee joint.

Laboratory Findings
• ESR : 82 mm at the end of 1 hr
• ASLO titre : positive up to 800 IU /ml
• CRP : 30 IU / L
• On Examination: Patient has pericardial friction rub, tachycardia and
arrhythmias
1.Interpret the results and give your diagnosis
2. Mention the criteria to make the above diagnosis
CHART- 15

1. Interpret the results and give your diagnosis

• A nine-year-old girl is having arthralgia, pericardial friction rub,
tachycardia and arrhythmias (involvement of heart), increased ESR,
positive ASLO titres and increased C reactive protein.
• Diagnosis: Rheumatic fever
2. Mention the criteria to make the above diagnosis
• Jones Criteria is used for the diagnosis of rheumatic fever
Major Criteria
• Migratory polyarthritis of large joints
• Pancarditis
• Subcutaneous nodules
• Erythema Marginatum
• Sydenham’s chorea
Minor Criteria
• Fever
• Arthralgia
• Increased ESR
• Increased or rising ASLO titres
• Increased C reactive protein levels
• Increased acute phase reactants
• Prolonged PR interval
For diagnosis: evidence of a preceding group A streptococcal infection, and the presence of two major
manifestations, or one major and two minor manifestations