ACUTE RHEUMATIC

FEVER (ARF)
 ACUTE RHEUMATIC FEVER (ARF):

• A multisystem disease resulting from an autoimmune

reaction to infection with group A streptococcus

• The incidence of RF has declined remarkably in the

industrialized countries of the world, where the
disease has become rare

• In many developing countries, which account for

almost 2/3 of the world’s population, streptococcal
infections, rheumatic fever (RF) and rheumatic
heart disease (RHD) remain a very significant
problem
 EPIDEMIOLOGY:

• ACUTE RHEUMATIC FEVER (ARF):

• Mainly a disease of children age 5-14 years
• No clear gender association

• RHEUMATIC HEART DISEASE (RHD):

• Prevalence peaks between 25 and 40 years
• More commonly affects females up to 2x as frequently as
males

• EPIDEMIOLOGIC RISK FACTORS:

• ARF and RHD are diseases of poverty
• The disease is more common among SOCIALLY and
ECONOMICALLY DISADVANTAGED populations with lower
standards of living and conditions of overcrowding
 PATHOGENESIS:

• I. ORGANISM FACTORS:
• Based on currently available evidence, ARF is exclusively
caused by infection of the upper respiratory tract with
group A streptococci

• II. HOST FACTORS:

• Susceptibility to ARF is an inherited characteristic
• HLA-DR7 and HLA-DR4: associated with susceptibility to ARF
• HLA-DR5, HLA-DR6, HLA-DR51, HLA-DR52, HLA-DQ:
associated with protection from ARF
 PATHOGENESIS:

III. THE IMMUNE RESPONSE:

• A. MOLECULAR MIMICRY
• The most widely accepted theory of RF pathogenesis

• An immune response targeted at streptococcal antigens (M PROTEIN and N-

ACETYLGLUCOSAMINE of group A streptococcal carbohydrate) also
recognizes human tissues

• Cross-reactive antibodies bind to endothelial cells on the heart valve,

leading to activation of the adhesion molecule VCAM-1, with resulting
recruitment of activated lymphocytes and lysis of endothelial cells in the
presence of complement

• Peptides (laminin, keratin, tropomyosin) released activate cross-reactive T

cells that invade the heart, amplifying the damage

• B. An alternative hypothesis proposes that the initial damage is due to

streptococcal invasion of epithelial surfaces, with binding of M protein
to type IV collagen, allowing it to become immunogenic
 CLINICAL FEATURES:

• There is a latent period of ~3 weeks (1-5 weeks)

between the precipitating group A streptococcal
infection and the appearance of the clinical
features

• Common manifestations:
• 1) polyarthritis- 60-75%
• 2) carditis- 50-60%
• 3) erythema marginatum
• 4) subcutaneous nodules
• 5) chorea
• 6) other: high-grade fever (>39 C) is the rule
 HEART INVOLVEMENT:
• Up to 60% of patients with ARF progress to RHD

• The endocardium, pericardium and myocardium may be affected

(PANCARDITIS)

• VALVULAR DAMAGE- hallmark of rheumatic carditis

• Mitral valve (MV) is almost always affected, sometimes together with the aortic valve
(AV)
• Isolated AV involvement is rare
• Pulmonary or tricuspid valve damage- secondary to increased pulmonary pressures
resulting from left-sided valvular disease
• Early valvular damage- regurgitation
• Recurrent valvular damage- leaflet thickening, scarring, calcification and valvular
stenosis

• MYOCARDIAL INFLAMMATION – affect electrical conduction pathways

leading to:
• P-R interval prolongation
• Softening of the first heart sound (S1)
 JOINT INVOLVEMENT:
• ARTHRITIS- the most common form of joint involvement

• Objective evidence of inflammation: hot, swollen, red and/or tender

joints

• Involvement of more than one joint (POLYARTHRITIS)

• Polyarthritis moves from one joint to another over a period of hours

(MIGRATORY)

• ARF almost always affects the LARGE JOINTS- knees, ankles, hips, elbows-
and is ASYMMETRIC

• The joint manifestations are highly responsive to salicylates and other

NSAIDs
 CHOREA:

• Sydenham’s chorea commonly occurs in the

absence of other manifestations, follows a
prolonged latent period after group A
streptococcal infection, and is found mainly in
females

• The choreiform movements affect particularly the

head (darting movements of the tongue) and the
upper limbs

• May be generalized or restricted to one side of the

body (hemi-chorea)
 SKIN MANIFESTATIONS:

• ERYTHEMA MARGINATUM:
• The classic rash of ARF
• Begins as pink macules that clear centrally, leaving a
serpiginous, spreading edge
• Evanescent
• Occurs usually on the trunk, sometimes on the limbs, but almost
never on the face

• SUBCUTANEOUS NODULES:
• Painless, small (0.5-2.0 cm), mobile lumps beneath the skin
overlying bony prominences of the hands, feet, elbows,
occiput and occasionally the vertebrae
• Appear 2-3 weeks after the onset of disease, last for just a few
days up to 3 weeks, and are commonly associated with
carditis
 RECOMMENDED TESTS IN CASES OF
POSSIBLE ARF:
• RECOMMENDED for ALL CASES:
• White blood cell count
• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP)
• Blood cultures if febrile
• Electrocardiogram (ECG)
• Chest x-ray
• Echocardiogram
• Throat swab (preferably before giving antibiotics)- culture for grp. A streptococcus
• Antistreptococcal serology: anti-streptolysin O (ASO) and anti-DNAse B titers (repeat
10-14 days later if first test not confirmatory)

• TESTS for ALTERNATIVE DIAGNOSES:

• Repeated blood cultures if possible endocarditis
• Joint aspirate (microscopy and culture) for possible septic arthritis
• Copper, ceruloplasmin, antinuclear antibody (ANA), drug screen for choreiform
movements
• Serology and autoimmune markers for arboviral, autoimmune or reactive arthritis
 DIAGNOSIS:

• There is no specific laboratory test that can establish

a diagnosis of RF- therefore, the DIAGNOSIS is
CLINICAL

• Supporting evidence from the clinical microbiology

and clinical immunology laboratories is required

• Because of the variety of clinical signs and

symptoms associated with the RF syndrome, in 1944
JONES first proposed criteria to assist the clinician in
standardizing the diagnosis of RF
THE 1992 REVISED JONES CRITERIA FOR
RHEUMATIC FEVER:
A. MAJOR CRITERIA:
• 1. Carditis
• 2. Migratory polyarthritis
• 3. Sydenham’s chorea
• 4. Erythema marginatum
• 5. Subcutaneous nodules

B. MINOR CRITERIA
1. Clinical: fever, polyarthralgia
2. Laboratory:
• elevated acute phase reactants (ESR) or leukocyte count
• prolonged PR interval

PLUS: supporting evidence of a recent grp. A strep infection within the last 45 days:
1. elevated or rising anti-streptolysin O (ASO) or other streptococcal antibody, or
2. a positive throat culture, or
3. rapid antigen test for group A streptococcus, or
4. recent scarlet fever
 2002-2003 WHO CRITERIA FOR THE
DIAGNOSIS OF RF AND RHD:
• 1. Primary episode of RF
• 2 major or 1 major and 2 minor manifestations plus evidence of preceding grp. A
streptococcal infection

• 2. Recurrent attack of RF in a patient without established RHD

• 2 major or 1 major and 2 minor manifestations plus evidence of preceding grp. A
streptococcal infection

• 3. Recurrent attack of RF in a patient with established RHD

• 2 minor manifestations plus evidence of preceding grp. A streptococcal infection

• 4. Rheumatic chorea or insidious onset rheumatic carditis

• Other major manifestations or evidence of grp. A streptococcal infection not required

• 5. Chronic valve lesions of RHD (patients presenting for the first time with
pure MS or mixed MV disease and/or AV disease)
• Do not require any other criteria to be diagnosed as having RHD
 TREATMENT:

2 THERAPEUTIC APPROACHES:

• I. ANTI-STREPTOCOCCAL ANTIBIOTIC THERAPY

• At the time of diagnosis, ALL patients with ARF should be
treated as if they have a grp. A strep infection, whether or not
the organism is recovered by culture

• PENICILLIN- drug of choice

• Oral Penicillin V or Phenoxymethylpenicillin 500mg BID x 10 days
• Benzathine Penicillin G 1.2 million units as a single IM injection

• Alternatives:
• ERYTHROMYCIN 250mg QID x 10 days
• AMOXICILLIN 500mg BID x 10 days
 TREATMENT:
II. THERAPY for the CLINICAL MANIFESTATIONS:

• A. SALICYLATES and NSAIDs

• Used for the treatment of arthritis, arthralgia and fever once the diagnosis is confirmed
• ASPIRIN- drug of choice
• Usual dose of 50-60mg/kg/day
• Maximum dose of 80-100mg/kg/day (4-8g/d in adults)
• NAPROXEN- alternative to aspirin
• 10-20mg/kg/day at a BID dosing

• B. PREDNISONE or PREDNISOLONE
• Treatment for severe carditis causing heart failure
• 1-2mg/kg/day (maximum: 80mg) up to a maximum duration of 3 weeks

• C. CARBAMAZEPINE or SODIUM VALPROATE

• Medications to control the abnormal movements of chorea

• D. INTRAVENOUS IMMUNOGLOBULIN (IVIG)

• Not usually recommended except in cases of severe chorea refractory to other treatments
 PROGNOSIS:

• Untreated, ARF lasts on average 12 weeks

• With treatment, patients usually improve within 1-2 weeks

• Inflammatory markers should be monitored every 1-2 weeks

until they have normalized (usually within 4-6 weeks)

• Echocardiogram should be performed after 1 month to

determine if there has been progression of carditis

• Once the acute episode has resolved, the priority in

management is to ensure long-term clinical follow-up and
adherence to a regimen of secondary prophylaxis
 PREVENTION:

• 1. PRIMARY PREVENTION:
• The mainstay remains primary prophylaxis, i.e., the timely
and complete treatment of group A streptococcal sore
throat with antibiotics
• Phenoxymethylpenicillin 500mg BID x 10 days
• Amoxicillin 1 gram daily
• Benzathine Penicillin G 1.2 million units IM as single dose

• 2. SECONDARY PREVENTION
• Benzathine Penicillin G 1.2 million units IM every 3 or 4 weeks
• Oral Penicillin V 250mg BID
• Erythromycin 250mg BID
 AHA RECOMMENDATIONS FOR
DURATION OF SECONDARY
PROPHYLAXIS
• 1. Rheumatic fever without carditis
• Treatment for 5 years after the last attack or 21 years of age
(whichever is longer)

• 2. Rheumatic fever with carditis but no residual valvular

disease
• Treatment for 10 years after the last attack or 21 years of age
(whichever is longer)

• 3. Rheumatic fever with persistent valvular disease

evident clinically or on echocardiography
• Treatment for 10 years after the last attack or 40 years of age
(whichever is longer), sometimes lifelong prophylaxis