Acute rheumatic fever

[Link]. Corina Zorilă

 Definition
• Acute rheumatic fever (ARF) is a systemic
disease of connective tissue, affecting various
organs (joints, heart, central nervous system,
skin), which occurs consecutively to a
streptococcalinfection (localized in the throat)
and has immune mechanism.
• The disease is especially important for the
consequences on the heart.
• ARF is the most common cause of heart disease
in children and young.
 Epidemiology
• The incidence is high in developing countries and
least developed.(in the Middle and Far
• East, Eastern Europe and South America and it is
rare in the UK, Western Europe and North America)
• In the U.S. the incidence decreased from
100/100000 inhabitants at the beginning of last
century to 2/100000 today. In Romania the
incidence is 8.4/100000.
• Maximum frequency is between 5-15 years of age,
the disease is very rare under 5 years and
exceptional under 3 years.
 Etiopathogeny
• The etiologic agent is group A beta-hemolytic
streptococc that can cause throat infections (angina),
serotypes 2,4, 8,21,22, 25,27,29.
• Rheumatogenic streptococci have a mucoid capsule rich
in hyaluronic acid and a rich cell wall in M protein ,
representing mucoid strains. Strong increase in these
mucoid strains is responsible for an increased incidence
of ARF, observed in developed countries in recent years.
• The disease occurs in intervals of 7-21 days after
streptococcal pharyngitis, this interval representing the
incubation period . Pharyngeal infection may be
asymptomatic in 30% of cases. Only 3% of angina is
followed by ARF.
 Phisiopathology
• 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 Streptococcus 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 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.
 The risk factors
• Factors that cause disease are related to the etiologic
agent (virulence / antigen) and the host organism. There
is a genetic predisposition detected by the presence of
HLA DRB 4, 8, 14.
• ARF occurs due to a hyperdimensional host immune
response to strep infection. In ARF, there are anti
antigens streptococcal antibodies (anti-M protein),
antigens which reacts with heart antigens or connective
tissue (myocardial sarcolemma, synovial membrane,
articular cartilage). In chorea neuronal antibodies are
present.
• Streptococcal superantigens (protein M, pyrogenic
exotoxin A, B, C) directly stimulates T cells then triggers
cellular and humoral response.
 Morphopathology
• In the acute phase – there is an exudative and
proliferative inflammatory reaction of the connective
tissue, especially involving the heart, joints, brain and
skin.
• ARF is often accompanied by a small vessel vasculitis,
but without thrombotic lesions.
• The pathognomonic lesion is considered to be the
Aschoff nodule = a proliferative granulomatous lesion
of the connective tissue.
•   appears in the myocardium, endocardium, periarticular,
in the skin, lymph nodes, etc..
• Aschoff nodules present in their. central area a fibrinoid
necrosis surrounded by mononuclear cells and
multinucleated giant cells
 Clinical Manifestations
• ARF begins within 7-21 days of a
streptococcal angina (latency period).
Pharyngeal infection may be
asymptomatic in 30% of cases.
ARF clinical manifestations:
• Major (carditis, polyarthritis, chorea,
subcutaneous nodules, and erythema)
• and a number of other actions are minor
diagnostic criteria.
 MAJOR CRITERIA
1. Polyarthritis
•Is the most common manifestation of the disease,
is benign and self-limiting in its evolution without
sequel.
•Arthritis is manifested by the presence of signs of
acute inflammation of the affected joint: erythema,
warmth, pain, swelling and disability.
•Affects large joints, is asymmetric, migrates,
persisting 3 days in a joint and covers a period of 3
weeks.
 2. Rheumatic carditis
• It is the most specific rheumatic manifestation. It can affect
any cardiac structures (pancarditis).
• Can occur concurrently with Arthritis or can precede or
succeed.
• Classic is described by cardiomegaly and cardiac murmurs,
and in severe forms of heart failure, pericardial friction rub.
• These signs occur in 40% of patients, but ultrasound
changes are seen in 90% of patients: valvular heart disease
due to ARF, implying especially the aortic and mitral valves
and pericardial effusion.
• Electrocardiographic signs from rheumatic myocarditis and
pericarditis are: tachycardia, PR interval lengthening,
widening QRS, ST-T segment changes and T wave.
 Inflammation of the valve
caused by rheumatic fever
• Is the most characteristic component of carditis.
• It is manifested by the appearance of new heart
murmurs, and mostly affects the aortic and mitral
valves and mitral chordae.
• Most commonly occurs mitral regurgitation,the
aortic regurgitation is less common.
• Repeated attacks of rheumatic fever causes
definitive valvular lesions, most commonly mitral
and aortic or even mitral-aortic implication.
• Myocarditis frequently accompanies
inflammation of the valves. Clinically
presentation: tachycardia, cardiomegaly,
and in severe forms heart failure signs.
• Pericarditis never appears alone and is
characterized by the accumulation of
pericardial fluid.
 3. Sydenham chorea

• Occurs in 15% of cases of ARF, being more common in

girls over 3 years.
• Occurs after a long latency period from the acute
pharyngeal episode (2 -6 months) and is always
preceded by a typical episode of ARF.
• Chorea is self-limiting with symptoms lasting 2-3 weeks.
It is manifested by:
• involuntary movements (flexion / extension of the
fingers, facial grimacing)
• motor incoordination (writing difficulties, speech
dysarthria, difficulty in performing fine movements)
• muscular hypotonia
• behavior disorders
 4. Erythema marginatum
• Has a low incidence, occurring in only 5%
of cases.
• Erythema marginatum manifests as a rash
macular pink, located on the skin covered,
non-itchy, which accentuates at warmth.
• At pressure the central area disappears,
leaving only the outline from where the
name of erythema marginatum .
 [Link] nodules
(Maynert)
• Are very rare, occurring in 3% of cases
• Nodule formations, hard, round, diameter
0.5-2 cm, painless which are localized on
the extensor surfaces of joints (elbows,
spinous processes, occiput).
• Accompanying severe forms of carditis.
 Minor criteria:
Clinical minor criteria:
•fever (38-39C) responding promptly to anti-
inflammatory treatment.
•arthralgia without signs of inflammation
•epistaxis and joint pain (may be present but
are not considered minor signs of ARF).
 Minor laboratory criteria:
• signs of inflammation (increased ESR, C-
reactive protein positive) are negative in the
corheea episod but positive during the acute
episode of ARF and correlates with clinical
outcome;
• lengthening of the PR interval on the
electrocardiogram is deemed as a minor sign of
ARF, but is (not) considered as a manifestation
of rheumatic carditis.
 Demonstration of streptococcal
infection
• Demonstration of pharyngeal infection can be done by:
-positive throat cultures,
-rapid detection of antigens Streptococcal
-detection of increased serum titers of anti-streptococcal
antibodies
• Positive throat cultures are rare due to the existence of
latent period and in some cases incomplete antibiotic
treatment that causes negativity cultures but does not
prevents ARF. This test does not distinguish between
healthy carriers and patients with streptococcal angina.
• Rapid streptococcal antigen detection (ELISA, Iatex) are
modern, rapid diagnostic tests for streptococcal infection.

• Detection of serum antibody titer of anti-streptococcal (ASOT) is

the more common method of demonstrating the post-infectious
immunological reaction.

•   The most commonly used are antistreptolysine O antibodies

(ASO or ASLO) which implies values ​above 200U/ml in 80% of
patients.

• By determining antibodies and antihyaluronidase and antidezoxi

ribonuclease B detection the percentage in detection increases
to 95%.
 Paraclinical examination
1. Laboratory tests:
•positive inflammatory tests:
•ESR> 50mm / h,
•rective protein C positive
•increased fibrinogen,
•increasing levels of IL1, IL2, TNF alpha, IgG, IgA,
•normal serum complement,
•Dilution anemia,
•leukocytosis with left shift.
 Electrocardiogram

• tachycardia,
• conduction disorders – prolonged PR
interval, various transient atrioventricular
blocks
• rhythm disturbances especially in the forms
with myocarditis,
• widening of the QRS complex, ST segment
changes and T wave..
 Chest radiograph:

• increasing cardiac volume - on account of

the present effusion or myocarditis,

• accentuation of broncho-vascular
markings
 Echocardiography:
• detects the presence of rheumatic
valvular damage, pericardial effusion,
and quantification of the correct size of
the cavities of the heart and
abnormalities in the walls motility
 Positive Diagnostic
• Positive diagnosis is based on Jones criteria,
introduced in 1944 and last revised in 1992. It is
sustained by the presence of:
• two major criteria,
• one major and two minor criteria,
• evidence of streptococcal infection is mandatory
(Table I).
 Revised Jones criteria
Major criteria Minore criteria Evidence of
streptococcal infection
carditis Clinic: Positive culture or rapid
polyarthritis > arthralgia test for streptococcal
Korea > fever antigen
Bordered laboratory: (ESR, CRP High or rising
Erythema positive) streptococcal antibody
subcutaneous PR interval against extracellular
nodules prolongation antigens
 DIFFERENTIAL DIAGNOSIS
• Rheumatoid arthritis,
• Other reactive arthritis,
• Lupus erythematosus
• Acute leukemia onset,
• Viral myocarditis,
• Kawasaki disease,
• Bacterial endocarditis, etc.
 Evolution
• The natural evolution of ARF is 2-3
months, with self-limiting evolution. The
severity of the episode is given from the
severity of rheumatic carditis.
• All impairment are autolimited with
excellent prognosis except valvular
endocarditis which can cause permanent
valvular sequelae.
After the acute episode may occur:

• rebound - the reappearance of clinical and biological

inflammatory phenomena due to premature
discontinuation of treatment;
• recurrence - a new flare of ARF precipitated by a new
streptococcal pharyngeal infection in a patient with at
least one rheumatic episode in the medical history,
pregnancy or use of oral contraceptives.
• It is common in the first 5 years after the first episode.
• The risk of recurrence is 15% and drops to 2-3% due to
secondary prevention of streptococcal infections. The
recurrence raise the risk of developing permanent
valvular lesions. If injuries of valvular insufficiency may
occur during an acute attack, then regress, vavular
stenosis develops after a few years.
 Primary prevention
• Primary prevention is to prevent the
occurrence of acute attacks ARF (first
episode) with prompt and correct
treatment of streptococcal angina. This
remarkably lowered incidence of ARF in
developed countries.
• Standard treatment of streptococcal
angina is penicillin G 1.2 million U / day, 7-
10 days, injectable.
Alternatives to the classical scheme
:
• benzatidin single dose penicillin 1.2 million U - the version
currently used,

• oral penicillin V 7-10 days 800 000 UI/24 hours 2-4 doses

• erythromycin allergic subjects - 40 mg / kg or

clarithromycin 10-15 mg / kg bw

• cephalosporin augmentin etc.

 Secondary prophylaxis;
• It addresses to the patients whom were sick after the first
rheumatic episode and consists of long-term prophylaxis
with penicillin. Prophylaxis regimens:
• benzatidin penicillin 1.2 million U every 3 weeks,
• oral penicillin V 400,000 U / day (250mg) until age 25,
then taking antibiotics before small or large surgery,
including dental.
• sulfadiazine 0.5-1 g / day
• erythromycin, 250-500 mg / day in patients with allergies.
• Duration of secondary prophylaxis is at least 5 years
after first episode or until at 18 years..
 Treatment in acute ARF
General measures:
•compulsory admission to hospital
•Bed rest is maintained through the entire
period with fever and with acute phase
reactants present
•exercise - will then be limited to patients
with moderate or severe carditis,
•in the presence of heart failure the use of
dietary salt restriction is considered.
 Antistreptococcal Therapy :

• Follows beta-hemolytic streptococc

eradication, even with negative cultures
schemes provided in primary prophylaxis,
followed by secondary prophylaxis.
 Anti-inflammatory therapy
• Aspirin - dose 100 mg / kg / day in the cases without carditis or mild
or moderate carditis. Duration of treatment:
• 6 weeks without carditis or in easy forms
• 8 weeks in moderate carditis
• 12 weeks in moderate carditis.
• Cortisteroids orally administered in severe carditis - 1 mg / kg / day
three weeks with tapering, possibly involving aspirin - 60 mg / kg to
prevent rebound phenomena.
• In the presence of heart failure will be given corticosteroid binding, 2
mg / kg / day.
• In case of rebound phenomena reduce corticosteroid doses (fever,
arthralgia, raised acute phase reactants), which does not respond to
symptomatic treatment should be given aspirin 75 mg / kg.
 Supportive and symptomatic
therapy:
In the presence of heart failure should be given
diuretics (especially furosemide) and cardiac
glycosides (with caution).
In chorea, the treatment will consist of:
•bed rest,
•anticonvulsant therapy with phenobarbital, sodium
valproate,
•haloperidol 0.5-2 mg / day
•not taking anti-inflammatory treatment.
Valvular surgery is recommended in patients with
severe valvular lesions, but not in acute episode..