ACUTE RHEUMATIC FEVER &

RHEUMATIC HEART DISEASE

Yrah Damiene M. Fernandez
Clinical Clerk

INTRODUCTION
RF and RHD remain significant

causes of cardiovascular diseases

in the world

medical and public health

problems in both industrialized and

industrializing countries even at
the beginning of the 21stcentury

RHD is the most common cause of

heart disease in children in

developing countries

Sub-Saharan Africa, Pacific

nations, Australasia, South and

Central Asia.

Clin Epidemiol. 2011; 3: 6784.

Published online 2011 Feb 22. doi: 10.2147/CLEP.S12977
The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease

EPIDEMIOLOGY
Global burden (about 2.4 mil) caused by rheumatic

fever and RHD

half a million new cases a year

300,000 who acquire ARF every year go on to develop RHD

Usually children and adolescents (5-14years old) living in

developing countries

233,000 deaths annually

More commonly in women (M:F1:2)
Clin Epidemiol. 2011; 3: 6784.
Published online 2011 Feb 22. doi: 10.2147/CLEP.S12977
The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease

MORTALITY BY CAUSE, AGE GROUP AND SEX NUMBER AND

RATE/100,000 POPULATION PHILIPPINES, 2011

ACUTE RHEUMATIC FEVER

diffuse inflammation of connective

tissues of heart, joints, brain, blood

vessels, and subcutaneous tissues

Autoimmune reaction due to Group

A beta-hemolytic streptococcal
infection

Almost all manifestation will resolve

completely

can cause persisting heart damage,

termed Rheumatic Heart Disease

(RHD)

FACTORS
Host
Organism

Environment

HOST FACTORS
ARF is an inherited characteristic
not hereditary, but predisposition to acquire infection is

genetic

HLA-DR5, HLA-DR6, HLA-DR52, and HLA-DQ-associated with

protection

HLA-DR7 and HLA-DR4- associated with susceptibility

Associations with polymorphisms at the tumor necrosis factor

locus (TNF--308 and TNF--238)

high levels of circulating mannose-binding lectin & Toll-like

receptors

ORGANISM

(GROUP A B-HEMOLYTIC STREPTOCOCCUS GABHS)

Cell wall group A carbohydrate
Mucoid strains (rheumatogenicity)

Cell wall M-proteins (virulence)

Serotypes 1,3,5,6,14,18,19 and 24

Superantigens: pyrogenic exotoxins

Enzymes: streptolysin, fibrinolysin, deoxyribonuclease

ETIOLOGY?

ETIOLOGY?

VIRULENCE
FACTOR
Streptolysin O

Streptolysin S

DESCRIPTION

An exotoxin, one of the

bases of the organism's
beta-hemolytic property
A cardiotoxic exotoxin,
another beta-hemolytic
component, not
immunogenic and O2
stable: A potent cell
poison affecting many
types of cell including
neutrophils, platelets, and
sub-cellular organelles,

VIRULENCE
FACTOR
Streptokinase

Hyaluronidase

DESCRIPTION
Enzymatically activates
plasminogen, a proteolytic
enzyme, into plasmin,
which in turn digests fibrin
and other proteins
facilitate the spread of the
bacteria through tissues by
breaking down hyaluronic
acid, an important
component of connective
tissue.

VIRULENCE FACTOR
Streptodornase

C5a Peptidase

DESCRIPTION
AKA DNases, which protect the
bacteria from being trapped in
neutrophil extracellular traps
(NETs) by digesting the NETs'
web of DNA
cleaves a potent neutrophil
chemotaxin called C5a, which
is produced by the
complement system which
minimizes the influx of
neutrophils early in infection as
the bacteria are attempting to
colonize the host's tissue.

VIRULENCE
FACTOR
Streptococcal
chemokine
protease

DESCRIPTION
Prevents the migration of
neutrophils to the
spreading infection. ScpC
degrades the chemokine
IL-8, which would otherwise
attract neutrophils to the
site of infection.

M PROTEIN (VIRULENCE)
M-protein is one of the best-

defined determinants of
bacterial virulence.

streptococcal M-protein extends

from the surface of the

streptococcal cell as an alpha
helical coiled coil dimer, and
shares structural homology with
cardiac myosin

this homology is responsible for

the pathological findings in

acute rheumatic carditis.

ENVIRONMENTAL FACTORS
Poor living conditions

Overcrowding
Poor access to health care

Seasonal variations

PATHOPHYSIOLOGY
develops following pharyngitis with group A beta-

hemolytic Streptococcus (ie, Streptococcus pyogenes)

incubation period of 2-4 days

acute inflammatory response with 3-5 days (sore throat,

fever, malaise, headache, and an elevated leukocyte

count)

PATHOPHYSIOLOGY
0.3-3% of cases, leads to rheumatic fever several weeks

after the sore throat has resolved.

latent period of ~3 weeks (15 weeks)

chorea and indolent carditis- lasting up to 6 months

PATHOPHYSIOLOGY
Precise mechanism is unknown
Two theories suggested

THEORIES
1. Cytotoxicity theory - GABHS produces several enzymes

streptolysin S & O*, that are directly cytotoxic for

mammalian cardiac cell

2. Immunologic theory - Autoimmune reaction to GABHS

produces pathogenic autoantibodies to cardiac tissues

DIAGNOSIS
No clinical or laboratory finding pathognomonic of RF
No definitive test

Relies on the presence of a combination of typical

clinical features together with evidence of the

precipitating group A streptococcal infection, and the
exclusion of other diagnoses

DIAGNOSIS
Evidence of preceeding GABHS +
2 major criteria or 1 major + 2minor manifestations

EVIDENCE OF PRECEEDING GABHS

An absolute requirement for the diagnosis of RF is the

supporting evidence of recent Group A strep infection

Throat culture may only be positive in 10-20% of px.

Elevated ASO titers is the basis in determining a previous

group A strep infection

35% of patients with RF do not have history of strep

infection (Markcquitz, 1972)

EVIDENCE OF RECENT STREPTOCOCCAL

INFECTION

HEART INVOLVEMENT
Up to 60% of patients with ARF progress to RHD
Endocardium, pericardium, or myocardium may be

affected

Pancarditis-> Most impt and serious finding in ARF

Valvular damage - hallmark of rheumatic carditis.

Mitral valve is almost always affected

Damage to the pulmonary or tricuspid valves

(secondary)

Early valvular damage leads to regurgitation

CARDITIS (REVIEW OF ANATOMY)

HEART
SOUNDS

Mitral Stenosis
Mitral regurgitation

Aortic regurgitation
Softening of S1
Prolonged P-R interval

REMEMBER:
Carditis is the single most important prognostic factor in

RF; only valvulitis leads to permanent damage and its

presence determines the prophylactic strategy

The clinical diagnosis of carditis in an index attack of RF is

based on the presence of significant murmurs,

pericardial rub, or an unexplained cardiomegaly with
CHF.

DIAGNOSIS OF RHEUMATIC CARDITIS

ECHOCARDIOGRAPHY
is an imaging technique, currently it is a key component in the diagnosis of heart disease
technique includes transthoracic, transesophageal and intracardiac echocardiography
Three-dimensional and even four-dimensional echocardiography have also been

developed

To diagnose rheumatic carditis and assess valvular disease, M-mode, two-dimensional

(2D), 2D echo-Doppler and colour flow Doppler echocardiography are sufficiently

sensitive and provide specific information not previously available.

M-mode echocardiography provides parameters for assessing ventricular function,

2D echocardiography provides a realistic real-time image of anatomical structure.
Two-dimensional echo-Doppler and colour flow Doppler echocardiography are most

sensitive for detecting abnormal blood flow and valvular regurgitation

MORPHOLOGY
During acute RF, focal inflammatory lesions are

found in various tissues

Distinctive lesions occur in the heart, called Aschoff

bodies, consisting of foci of T lymphocytes,

occasional plasma cells, and plump activated
macrophages called Anitschkow cells
(pathognomonic for RF).

ASCHOFF GIANT CELLS

 These macrophages have

abundant cytoplasm and

central round-to-ovoid
nuclei (occasionally
binucleate) in which the
chromatin condenses into
a central, slender, wavy
ribbon (hence the
designation caterpillar
cells)

VERRUCAE
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.

 Subendocardial lesions,

perhaps exacerbated by
regurgitant jets, can
induce irregular
thickenings called
MacCallum plaques,
usually in the left atrium.

JOINT INVOLVEMENT
Arthritis (75%)
Affects the large jointsknees, anklesand is

asymmetric.

Hot, Swollen, Red, Tender, Polyarthritis, Migratory

The pain is severe, disabling

 Relieved by anti-inflammatory medication (NSAIDs,

salicylates)

most frequent major manifestation of RF

aspirated sample of synovial fluid may reveal a high

average leukocyte count (29000mm-3 , range 200096

000mm-3 )

CHOREA
536%
prolonged latent period

emotional lability
uncoordinated movements

muscular weakness

SIGNS
pronator (tendency to pronate the hands when extending

the arms above the head)

spoon or dish (flexion and dorsal arching of the wrists and

hyperextension of the fingers when the hands are extended

sideways palms down)

milkmaids grip (involuntary, repetitive squeezing motion)

darting tongue (difficulty keeping tongue protruded,

involuntary movement of the tongue where it looks like its

popping in and out)

changes in handwriting

 choreiform movements disappear during sleep,

decrease with rest and sedation, and can be

suppressed by volition for few movements

Onset can be insidious

Occasionally unilateral, most bilateral

Females more affected; rare after age 20 years old

 Rarely leads to permanent sequelae

Longer latency: 1-7 months (2-4 months) remind parents

that it is not permanent, but carditis is, because of the long

latency period, the patient may have normal ASO titer

Duration: 1wk to >2 yrs (median 15 wks; within 6 months)

May wax and wane

(+) strep. Infection in only 2/3 of cases
One criterion that can stand alone

SKIN MANIFESTATION
Erythema Marginatum (<3%)

-rare

begins as pink macules that

clear centrally, leaving a

serpiginous, spreading edge.
evanescent, appearing and
disappearing before the
examiners eyes.
trunk, limbs, but almost never on
the face.

 Subcutaneous nodules
painless, small (0.52 cm), mobile
lumps beneath the skin overlying
bony prominences (hands, feet,
elbows, occiput, and occasionally
the vertebrae.
delayed manifestation, appearing
23 weeks after the onset
last for just a few days up to 3 weeks
commonly associated with carditis.

REMEMBER
Subcutaneous nodules are almost always associated

with cardiac involvement and are found more

commonly in patients with severe carditis.

MANAGEMENT

PRIMARY PREVENTION
defined as the adequate antibiotic therapy of group A

streptococcal upper respiratorytract (URT) infections to

prevent an initial attack of acute RF

administered only when there is group Astreptococcal

URT infection

therapy is intermittent

SECONDARY PREVENTION
defined as continuous administration of specific antibiotics
patients with a previous attack of RF, or a well-documented

rheumatic heart disease (RHD)

to prevent colonization or infection of the upper respiratory

tract (URT) with group A beta-hemolytic streptococci and

development of recurrent attacks of RF

Secondary prophylaxis is mandatory for all patients who have

had an attack of RF, whether or not they have residual

rheumatic valvular heart disease

DURATION OF SECONDARY PROPHYLAXIS

factors influencing the risk of RF recurrence:
the age of the patient
the presence of RHD
the time elapsed from the last
attack

the socioeconomic and

educational status of the individual
the risk of streptococcal infection
in the area

the number of previous attacks

whether a patient is willing to

receive injections

the degree of crowding in the

family

the occupation and place of

employment of the patient (school

a family history of RF/RHD

teachers, physicians, employees in

crowded areas).

26-VALENT AND 30-VALENT M PROTEIN

VACCINES
The 26-valent vaccine underwent a phase I/II clinical trial in human adult

volunteers and was shown to be safe and immunogenic [14].

Functional opsonic antibodies were induced against all emm types of

GAS in the vaccine

reformulated into a 30-valent vaccine to increase coverage of

circulating emm types in the United States, Canada and Europe as well
as developing countries.

Epidemiologic surveys suggest that the 26-valent vaccine would provide

good coverage of circulating strains of GAS in industrialized countries

(over 72%) but poor coverage in many developing countries (as low as
24% in the Pacific region).

In preclinical studies, the 30-valent vaccine has been shown to induce

functional opsonic antibodies against all emm types of GAS represented

in the vaccine. A

CONSERVED M PROTEIN VACCINES

These vaccines contain antigens from the conserved C-

repeat portion of the M protein.

The StreptInCor vaccine incorporates selected T and B-cell

epitopes from the C-repeat region, whereas the J8 and J14

vaccines contain single minimal B cell epitopes from this
same region.

Extensive studies in mice, particularly of the J8 vaccine

candidate, have shown that these antigens produce

opsonic antibodies that protect against challenge.

The J8 vaccine has recently entered a phase 1 trial in adult

volunteers.

RHEUMATIC HEART
DISEASE
Recurrences of ARF cause

further valve damage,

leading to worsening of
RHD

Most serious sequel of

rheumatic fever

MORPHOLOGY

Mitral valve alone - 65% to 70%

Mitral + Aortic - 25% of cases.
Tricuspid valve - infrequent
Pulmonary valve - rare

PHYSICAL ASSESSMENT

INSPECTION: heaves
PERCUSSION
PALPATION: pulsation, thrill, lifts
AUSCULATION: S1, S2, murmur

AUSCULTATION

AUSCULTATION

ASSESSMENT OF MURMUR
Is there a murmur?
When is it heard?
Where is it located?
Does it radiate? Where?
What is the shape?
What is the pitch?
What is the intensity/grade?

What is the quality?

What is the response to maneuver

TIMING

Systole

S1---------- S2---------------S1

2 components
Rapid Ejection

Slow Ejection
Diastole

S1---------- S2---------------S1

3 components

Early (Rapid Filling)

Middle
Late

LOCATION/RADIATION

SHAPE

PITCH
HIGH - High Pressure Gradients (VSD)
LOW Large Volume across low pressure gradients

(Mitral Stenosis)

HARSH High Pressure Gradient + Large Volume of flow

(Aortic Stenosis)

QUALITY
Subjective

Blowing?
Musical?

Rumbling?
Harsh?

Machine Like?

RESPONSE TO MANEUVERS

INTENSITY

MITRAL INSUFFICIENCY
Loss of valvular substance
shortening and thickening of the chordae tendineae

MITRAL INSUFFICIENCY
Spontaneous improvement usually occurs with time
Patient is asymptomatic (Quiet Precordium)
More than half of patients with acute mitral

insufficiency no longer have the mitral murmur 1 yr

later

MITRAL INSUFFICIENCY
High-pitched holosystolic murmur at
the apex that radiates to the axilla
Heart is enlarged, with a heaving apical
left ventricular impulse and often an
apical systolic thrill
2nd heart sound may be accentuated if
pulmonary hypertension is present
3rd heart sound is generally prominent

MITRAL INSUFFICIENCY
Short mid-diastolic rumbling murmur is
caused by increased blood flow across
the mitral valve as a result of insuff.
ECG: Prominent Bifid P waves ; signs
of LVH and RVH if hypertension is
present

MITRAL INSUFFICIENCY
Mild - prophylaxis against RF
Afterload-reducing agents (ACE inhibitors or

ARBs) may reduce the regurgitant volume and

preserve left ventricular function
Surgical treatment: annuloplasty or valve
replacement

MITRAL STENOSIS
Results from fibrosis of the mitral ring,

commissural adhesions, and contracture of the

valve leaflets, chordae, and papillary muscles over
time

Usually takes 10 yr or more for the lesion to become

fully established

increased pressure and enlargement

and hypertrophy of the left atrium

pulmonary venous hypertension,

increased pulmonary vascular
resistance, and pulmonary
hypertension

Right ventricular hypertrophy and

right atrial dilatation ensue

RV dilation, tricuspid regurgitation,

and clinical signs of right-sided heart
failure

MITRAL STENOSIS
Mild - asymptomatic
Severe - exercise intolerance and
dyspnea;
Critical - orthopnea, paroxysmal
nocturnal dyspnea, overt pulmonary
edema, atrial arrhythmias.
pulmonary hypertension/right
ventricular dilatation - functional
tricuspid insufficiency, hepatomegaly,
ascites, and edema

MITRAL STENOSIS
Hemoptysis caused by rupture of bronchial or

pleurohilar veins and, occasionally , by pulmonary

infarction may occur

MITRAL STENOSIS
Parasternal right ventricular lift
Loud 1st heart sound, an opening snap of the mitral

valve, and a long, low-pitched, rumbling mitral

diastolic murmur with presystolic accentuation at
the apex (Absent in significant heart failure)

MITRAL STENOSIS
A holosystolic murmur sec to tricuspid
insuff. may be audible
Pulmonic component of S2 is
accentuated due to presence of pul.
HPN
An early diastolic murmur may be
caused by associated aortic insuff. or
pulmonary valvular insuff sec. to pulm.
HPN

MITRAL STENOSIS
ECG
1. Severe: Notched P waves and Varying
degrees of RVH
2. Atrial Fibrillation is a common late
manifestation

MITRAL STENOSIS
Symptomatic
Surgical valvotomy or balloon catheter
mitral valvuloplasty
Valve replacement is avoided unless
absolutely necessary
Balloon valvuloplasty is indicated for
symptomatic, stenotic, pliable,
noncalcified valve of patients without
atrial arythmias or thrombi

AORTIC INSUFFICIENCY
Sclerosis of the aortic valve results in distortion

and retraction of the cusps

Regurgitation of blood leads to volume overload
with dilatation and hypertrophy of the left ventricle
Combined mitral and aortic insuff > aortic
involvement alone

AORTIC INSUFFICIENCY
Symptoms are unsual except in severe
Palpitations, sweating and heat intolerance
Dyspnea on exertion

AORTIC INSUFFICIENCY
Wide pulse pressure, bounding peripheral pulses
Left ventricular apical heave and diastolic thrill

AORTIC INSUFFICIENCY
Typical murmur begins immediately with the 2nd

heart sound and continues until late in diastole;

heard over the upper and midleft sternal border
with radiation to the apex and upper right sternal
border
high-pitched blowing quality, easily audible in full
expiration

AORTIC
INSUFFICIENCY
Aortic
Systolic Ejection Murmur is
frequent because of Increased Stroke
Volume
An apical presystolic murmur (Austin
Flint Murmur) resembling that of
mitral stenosis is sometimes heard and is
a result of the large regurgitant aortic
flow in diastole preventing the mitral
valve from opening fully

Sign
Becker Sign

Description
Visible systolic pulsations of the retinal
arterioles
Corrigan pulse ("water- Abrupt distention and quick collapse on
hammer" pulse)
palpation of the peripheral arterial pulse
de Musset sign
Hill sign

Duroziez sign

Mller sign
Quincke sign

Bobbing motion of the patient's head with

each heartbeat
Popliteal cuff systolic blood pressure 40 mm
Hg higher than brachial cuff systolic blood
pressure
Systolic murmur over the femoral artery
with proximal compression of the artery,
and diastolic murmur over the femoral
artery with distal compression of the artery
Visible systolic pulsations of the uvula
Visible pulsations of the fingernail bed with
light compression of the fingernail

Traube sign ("pistol-shot" Booming systolic and diastolic sounds

AORTIC
INSUFFICIENCY
ECG:
LVH
Strain with prominent P waves

AORTIC
INSUFFICIENCY
does
not regress; combined lesions
during the episode of acute rheumatic
fever may have only aortic involvement
1-2 yr later
afterload reducers and prophylaxis
against recurrence of acute rheumatic
fever
surgical intervention before
complications

TRICUSPID VALVE DISEASES

Rare after rheumatic fever
More common secondary to right ventricular

dilatation resulting from unrepaired left-sided

lesions

TRICUSPID VALVE DISEASES

Prominent pulsations of the jugular veins, systolic

pulsations of the liver, and a blowing holosystolic

murmur at the lower left sternal border that
increases in intensity during inspiration.

Tricuspid valvuloplasty m ay be required in rare

cases.

PULMONARY VALVE DISEASES

Pulmonary insufficiency usually occurs on a

functional basis secondary to pulmonary

hypertension

Late finding with severe mitral stenosis

PULMONARY VALVE DISEASES

Murmur (Graham Steell murmur) is similar to that

of aortic insufficiency , but peripheral arterial sign

are absent.

The correct diagnosis is confirmed by two-

dimensional echocardiography and Doppler studies