Acute Rheumatic Fever
• Acute rheumatic fever (ARF) is a multisystem disease resulting
from an autoimmune reaction to infection with group A
streptococcus.
• Although many parts of the body may be affected, almost all of
the manifestations resolve completely. The major exception is
cardiac valvular damage (rheumatic heart disease [RHD]), which
may persist after the other features have disappeared.
EPIDEMIOLOGY
• ARF is mainly a disease of children age 5–14 years.
• Initial episodes become less common in older adolescents and
young adults and are rare in persons aged >30 years. By contrast,
recurrent episodes of ARF remain relatively common in adolescents
and young adults. This pattern contrasts with the prevalence of
RHD, which peaks between 25 and 40 years.
• There is no clear gender association for ARF, but RHD more
commonly affects females, sometimes up to twice as frequently as
males.
PATHOGENESIS
ORGANISM FACTORS HOST FACTORS THE IMMUNE RESPONSE
ARF is exclusively • susceptibility to ARF (particularly for The most widely accepted theory
caused by infection of chorea) is an inherited characteristic, with of rheumatic fever pathogenesis
the upper respiratory 44% concordance in mono-zygotic twins is based on the concept of
tract with group A compared to 12% in dizygotic twins, and molecular mimicry, whereby an
streptococci. heritability more recently estimated at immune response targeted at
(particularly M- 60%. streptococcal antigens (mainly
serotypes 1, 3, 5, 6, • Susceptible HLA-DR7 and HLA-DR4 . thought to be on the M protein
14, 18, 19, 24, 27, and • Protective (HLA-DR5, HLA-DR6, and the N-acetylglucosamine of
29) HLA-DR51, HLA-DR52, and HLA-DQ). group A streptococcal
• Associations have also been described carbohydrate) also recognizes
with polymorphisms at the tumor necrosis human tissues.
factor α locus (TNF-α-308 and TNF-α-
238), high levels of circulating mannose-
binding lectin, and Toll-like receptors.
THE IMMUNE RESPONSE
• The most widely accepted theory of rheumatic fever pathogenesis is based on the
concept of molecular mimicry, whereby an immune response targeted at streptococcal
antigens (mainly thought to be on the M protein and the N-acetylglucosamine of group
A streptococcal carbohydrate) also recognizes human tissues.
• In this model, 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.
The latter leads to release of peptides including laminin, keratin, and tropomyosin,
which, in turn, activates cross-reactive T cells that invade the heart, amplifying the
damage and causing epitope spreading.
• 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, but not through the mechanism of molecular mimicry
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 of ARF. The
exceptions are chorea and indolent carditis, which may follow prolonged latent
periods lasting up to 6 months.
• Although many patients report a prior sore throat, the preceding group A
streptococcal infection is commonly subclinical; in these cases, it can only be
confirmed using streptococcal antibody testing.
• The most common clinical features are polyarthritis (present in 60–75% of
cases) and carditis (50–60%). The prevalence of chorea in ARF varies
substantially between populations, ranging from <2 to 30%. Erythema
marginatum and subcutaneous nodules are now rare, being found in <5% of
cases.
HEART INVOLVEMENT
• Up to 60% of patients with ARF progress to RHD.
• The endocardium, pericardium, or myocardium may be affected.
• Valvular damage is the hallmark of rheumatic carditis. The mitral valve is almost always affected,
sometimes together with the aortic valve; isolated aortic valve involvement is rare. Damage to the
pulmonary or tricuspid valves is usually secondary to increased pulmonary pressures resulting from left-
sided valvular disease.
• Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent
episodes,leaflet thickening, scarring, calcification, and valvular stenosis may develop . Therefore, the
characteristic manifestation of carditis in previously unaffected individuals is mitral regurgitation,
sometimes accompanied by aortic regurgitation.
• Myocardial inflammation may affect electrical conduction pathways, leading to P-R interval prolongation
(first-degree atrioventricular block or rarely higher level block) and softening of the first heart sound.
• People with RHD are often asymptomatic for many years before their valvular disease progresses to cause
cardiac failure.
JOINT INVOLVEMENT
• The most common form of joint involvement in ARF is arthritis, i.e., objective evidence of
inflammation, with hot, swollen, red, and/or tender joints, and involvement of more than one
joint (i.e., polyarthritis).
• Polyarthritis is typically migratory, moving from one joint to another over a period of hours.
• ARF almost always affects the large joints—most commonly the knees, ankles, hips, and elbows
—and is asymmetric. The pain is severe and usually disabling until anti-inflammatory medication
is commenced.
• Less severe joint involvement is also relatively common and has been recognized as a potential
major manifestation in high-risk populations in the most recent revision of the Jones criteria.
• Arthralgia without objective joint inflammation usually affects large joints in the same migratory
pattern as polyarthritis. In some populations, aseptic monoarthritis may be a presenting feature of
ARF, which may, in turn, result from early commencement of anti-inflammatory medication
before the typical migratory pattern is established.
• The joint manifestations of ARF are highly responsive to salicylates and other nonsteroidal anti-
inflammatory drugs (NSAIDs). Indeed, joint involvement that persists for more than 1 or 2
days after starting salicylates is unlikely to be due to ARF.
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 (causing characteristic
darting movements of the tongue) and the upper limbs. They may be
generalized or restricted to one side of the body (hemi-chorea).
• In mild cases, chorea may be evident only on careful examination, whereas in
the most severe cases, the affected individuals are unable to perform activities
of daily living.
• There is often associated emotional lability or obsessive-compulsive traits,
which may last longer than the choreiform movements (which usually resolve
within 6 weeks but sometimes may take up to 6 months).
SKIN MANIFESTATIONS
• The classic rash of ARF is erythema marginatum , which begins as
pink macules that clear centrally, leaving a serpiginous, spreading
edge. The rash is evanescent, appearing and disappearing before the
examiner’s eyes. It occurs usually on the trunk, sometimes on the
limbs, but almost never on the face.
• Subcutaneous nodules occur as painless, small (0.5–2 cm), mobile
lumps beneath the skin overlying bony prominences, particularly of
the hands, feet, elbows, occiput, and occasionally the vertebrae. They
are a delayed manifestation, appearing 2–3 weeks after the onset of
disease, last for just a few days up to 3 weeks, and are commonly
associated with carditis.
OTHER FEATURES
• Fever occurs in most cases of ARF, although rarely in cases of pure
chorea. Although high-grade fever (≥39°C) is the rule, lower grade
temperature elevations are not uncommon.
• Elevated acute-phase reactants are also present in most cases.
EVIDENCE OF A PRECEDING GROUP A
STREPTOCOCCAL INFECTION
• With the exception of chorea and low-grade carditis, both of which may become
manifest many months later, evidence of a preceding group A streptococcal infection is
essential in making the diagnosis of ARF.
• Because most cases do not have a positive throat swab culture or rapid antigen test,
serologic evidence is usually needed.
• The most common serologic tests are the anti-streptolysin O (ASO) and anti-DNase
B (ADB) titers. Where possible, age-specific reference ranges should be determined in
a local population of healthy people without a recent group A streptococcal infection.
CONFIRMING THE DIAGNOSIS
• Because there is no definitive test, the diagnosis of ARF 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.
• This uncertainty led Dr. T. Duckett Jones in 1944 to develop a set of criteria
(subsequently known as the Jones criteria) to aid in the diagnosis. The most
recent revision of the Jones criteria require the clinician to determine if the
patient is from a setting or population known to experience low rates of
ARF. For this group, there is a set of “low-risk” criteria; for all others,
there is a set of more sensitive criteria.
Jones Criteria
MANAGEMENT
• Patients with possible ARF should be followed closely to ensure that the
diagnosis is confirmed, treatment of heart failure and other symptoms is
undertaken, and preventive measures including commencement of secondary
prophylaxis, inclusion on an ARF registry, and health education are
commenced.
• Echocardiography should be performed on all possible cases to aid in making
the diagnosis and to determine the severity at baseline of any carditis. Other
tests that should be performed are listed in Table 352-3.
• There is no treatment for ARF that has been proven to alter the likelihood of
developing, or the severity of, RHD. With the exception of treatment of heart
failure, which may be life-saving in cases of severe carditis, the treatment of
ARF is symptomatic.
INVESTIGATION
S
TREATMENT
Acute Rheumatic Fever
ANTIBIOTICS - SALICYLATES AND NSAIDs
All patients with ARF should receive These may be used for the treatment of arthritis, arthralgia, and
antibiotics sufficient to treat the fever, once the diagnosis is confirmed. They are of no proven
precipitating group A streptococcal value in the treatment of carditis or chorea.
infection . Penicillin is the drug of choice Aspirin is the drug of choice, delivered at a dose of 50–60
and can be given orally (as phenoxymethyl mg/kg per day, up to a maximum of 80–100 mg/kg per day (4–8
penicillin, 500 mg [250 mg for children g/d in adults) in 4–5 divided doses.
≤27 kg] PO twice daily, or amoxicillin, 50 At higher doses, the patient should be monitored for symptoms of
mg/kg [maximum, 1 g] daily, for 10 days) salicylate toxicity such as nausea, vomiting, or tinnitus; if
or as a single dose of 1.2 million units symptoms appear, lower doses should be used .
(600,000 units for children ≤27 kg) IM Naproxen at a dose of 10–20 mg/kg per day is a suitable
benzathine penicillin G. alternative to aspirin and has the advantage of twice-daily
dosing.
TREATMENT
HEART FAILURE CHOREA
Bed rest • Milder cases can usually be managed by providing a
Low salt & fluid restriction calm environment.
Diuretics • In patients with severe chorea, carbamazepine or
Corticosteroids -Many clinicians treat cases sodium valproate is preferred to haloperidol.A response
of severe carditis (causing heart failure) may not be seen for 1–2 weeks, and medication should
with glucocorticoids in the belief that they be continued for 1–2 weeks after symptoms subside.
may reduce the acute inflammation and • There is recent evidence that corticosteroids are
result in more rapid resolution of failure. effective and lead to more rapid symptom reduction in
chorea. They should be considered in severe or
refractory cases.
• INTRAVENOUS IMMUNOGLOBULIN (IVIG )- In
the absence of better data, IVIg is not recommended
except in cases of severe chorea refractory to other
treatments.
PROGNOSIS
• Untreated, ARF lasts on average 12 weeks. With treatment, patients are usually
discharged from hospital within 1–2 weeks. Inflammatory markers should be
monitored every 1–2 weeks until they have normalized (usually within 4–6 weeks),
and an echocardiogram should be performed after 1 month to determine if there
has been progression of carditis. Cases with more severe carditis need close
clinical and echocardiographic monitoring in the longer term.
• 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.
• Patients should be entered onto the local ARF registry (if present) and contact
made with primary care practitioners to ensure a plan for follow-up and
administration of secondary prophylaxis before the patient is discharged. Patients
and their families should also be educated about their disease, emphasizing the
importance of adherence to secondary prophylaxis.
PREVENTION
PRIMARY PREVENTION- SECONDARY PREVENTION-
• mainstay of primary prevention
for ARF remains primary
prophylaxis (i.e., the timely and
complete treatment of group A
streptococcal sore throat with
antibiotics). If commenced
within 9 days of sore throat
onset, a course of penicillin (as
outlined above for treatment of
ARF) will prevent almost all
cases of ARF that would
otherwise have developed.
Thank you
