Acute Rheumatic Fever (ARF)

• ARF is a multisystem disease resulting from an autoimmune reaction to infection with group A Streptococcus.
• Affected Systems: Many parts of the body may be involved.
• Resolution: Almost all manifestations resolve completely.
• Exception: Cardiac valvular damage (rheumatic heart disease [RHD]) may persist even after other features of ARF
disappear

Global Considerations of ARF and RHD

• Diseases of Poverty: ARF and RHD are strongly associated with poverty, overcrowded living conditions, poor
hygiene, and inadequate healthcare access.
• Decline in Industrialized Nations:
o Incidence declined in the early 20th century due to improved living conditions, hygiene, antibiotics, and
better healthcare systems.
• Persistence in Developing Countries:
o RHD remains the most common cause of acquired heart disease in children and a significant cause of
morbidity and mortality in adults.
o 95% of ARF and RHD cases occur in developing countries, with high rates in sub-Saharan Africa,
Pacific nations, Australasia, and South and Central Asia.
• Global Burden:
o Estimated 29.7–43.1 million people affected worldwide.
o Over 300,000 deaths annually.
• Key Risk Factors:
o Overcrowded living conditions, poverty, rural/urban slum residence.
o Asymptomatic infections, failure to seek healthcare, and inadequate or failed treatment of streptococcal
pharyngitis.
• Challenges in Control:
o Lack of resources, capacity, and organized RHD control programs in developing countries.
o Few countries have cost-effective, register-based RHD control programs.
• Call to Action:
o Enhancing awareness and mobilizing resources for RHD control requires international attention and
action.
Epidemiology of ARF and RHD
• Age Groups Affected:
o ARF primarily affects children aged 5–14 years.
o Initial episodes are rare in individuals aged >30 years.
o Recurrent ARF episodes are more common in adolescents and young adults.
• RHD Prevalence:
o Peaks between 25 and 40 years of age.
• Gender Differences:
 o No clear gender association for ARF.
o RHD is more common in females, sometimes up to twice as frequent as in males.

Pathogenesis of ARF
• Causative Agent: ARF is caused by group A streptococcal infections, primarily of the upper respiratory tract.
• M-Serotypes: Classical M-serotypes (e.g., types 1, 3, 5, 6, 14, 18, 19, 24, 27, 29) were traditionally linked to ARF,
but many more serotypes are now recognized as rheumatogenic.
• Skin Infection: Recent evidence suggests a significant role for skin infections in ARF pathogenesis.
• Unclear Role: The contribution of groups C and G streptococci to ARF remains uncertain.

Host Factors in ARF

• Susceptibility:
o 3–6% of any population is genetically susceptible to ARF, consistent across populations.
o Susceptibility is an inherited trait, with:
▪ 44% concordance in monozygotic twins.
▪ 12% concordance in dizygotic twins.
▪ Heritability estimated at 60%.
• Genetic Associations:
o HLA Class II Alleles:
▪ Susceptibility linked to HLA-DR7 and HLA-DR4.
▪ Protection associated with HLA-DR5, HLA-DR6, HLA-DR51, HLA-DR52, and HLA-DQ.
o Other Genetic Markers:
▪ Polymorphisms at TNF-α loci (TNF-α-308, TNF-α-238).
▪ High levels of mannose-binding lectin.
▪ Variants in Toll-like receptors.
▪ Genome-wide studies link ARF susceptibility to HLA-DQA1 to HLA-DQB1 and
the immunoglobulin heavy chain locus.
• Focus on Immunology: Most evidence suggests that susceptibility to ARF is driven by immunologic determinants.
the Immune Response in ARF
• Molecular Mimicry:
o The leading theory for ARF pathogenesis involves an immune response targeting streptococcal
antigens(e.g., M protein and N-acetylglucosamine) that cross-reacts with human tissues.
• Mechanism of Damage:
o Cross-reactive antibodies bind to endothelial cells on heart valves.
o This activates VCAM-1, recruiting lymphocytes and causing:
▪ Endothelial cell lysis (via complement).
▪ Release of peptides like laminin, keratin, and tropomyosin, which activate T cells and amplify
damage.
o Results in epitope spreading and ongoing tissue damage.
• Alternative Hypothesis:
 o Suggests initial damage from streptococcal invasion of epithelial surfaces.
o M protein binds to type IV collagen, triggering immunogenicity independent of molecular mimicry.

Clinical Features of ARF

• Latent Period:
o ~3 weeks (range: 1–5 weeks) after group A streptococcal infection.
o Exceptions:
▪ Chorea and indolent carditis can have latent periods of up to 6 months.
• Preceding Infection:
o Often subclinical and confirmed only by streptococcal antibody testing.
• Common Clinical Features:
o Polyarthritis: Present in 60–75% of cases.
o Carditis: Present in 50–75% of cases.
• Variable Features:
o Chorea: Prevalence varies from <2% to 30% depending on the population.
o Erythema marginatum and subcutaneous nodules: Rare, found in <5% of cases.

Heart Involvement in ARF

• Progression to RHD: Up to 75% of ARF patients develop rheumatic heart disease (RHD).
• Valvular Damage:
o Mitral valve is almost always affected; may also involve the aortic valve.
o Isolated aortic valve involvement is rare.
o Damage to pulmonary or tricuspid valves is usually secondary to left-sided valvular disease.
• Early Damage: Causes valvular regurgitation.
• Chronic Damage: Recurrent episodes lead to:
o Leaflet thickening, scarring, calcification, and stenosis.
• Characteristic Manifestation:
o Mitral regurgitation, often with aortic regurgitation.
o May include P-R interval prolongation (first-degree AV block) and softening of the first heart sound.
• Asymptomatic Phase:
o Patients may remain asymptomatic for years before valvular disease causes cardiac failure.
o Echocardiography is crucial for diagnosis in asymptomatic cases, especially in resource-poor settings.
• Screening and Diagnosis:
o Portable echocardiography and consensus guidelines enable early detection in high-risk populations.
o Borderline RHD diagnosis requires further clarification of clinical significance.
• Prophylaxis: A confirmed diagnosis of RHD on echocardiography warrants secondary prophylaxis to prevent
further damage.
Joint Involvement in ARF
• Common Manifestation:
o Arthritis (inflammation with hot, swollen, red, and/or tender joints) is the most common joint
manifestation.
o Typically migratory polyarthritis, moving between joints over hours.
• Pattern:
o Asymmetric and affects large joints (knees, ankles, hips, elbows).
o Pain is severe and often disabling until treatment begins.
• Other Forms:
o Arthralgia: Joint pain without inflammation, following a similar migratory pattern.
o Aseptic monoarthritis: May occur, especially if anti-inflammatory medication is started early.
• Diagnosis and Treatment:
o Responsive to NSAIDs or salicylates: Symptoms resolving within 1–2 days of treatment are
characteristic of ARF.
o Persistent joint symptoms beyond 1–2 days of treatment are unlikely to be due to ARF.
• High-Risk Populations:
o Recent revisions of the Jones criteria recognize less severe joint involvement as a potential major
manifestation in high-risk populations.

Chorea in ARF
• Sydenham's Chorea:
o Often occurs without other ARF manifestations.
o Follows a prolonged latent period after group A streptococcal infection.
o More common in females.
• Choreiform Movements:
o Primarily affect the head (darting tongue movements) and upper limbs.
o May be generalized or unilateral (hemi-chorea).
o In mild cases, movements are subtle; in severe cases, they interfere with daily activities.
• Associated Symptoms:
o Emotional lability or obsessive-compulsive traits may persist beyond the chorea.
o Chorea usually resolves within 6 weeks, but sometimes takes up to 6 months.
• Carditis Link:
o Over 50% of patients with chorea also have carditis.
o Echocardiography should be part of the diagnostic workup.

Skin Manifestations in ARF

• Erythema Marginatum:
o Classic rash beginning as pink macules that clear centrally, leaving a serpiginous edge.
 o Evanescent rash: Appears and disappears rapidly.
o Commonly located on the trunk, sometimes on the limbs, but rarely on the face.
• Subcutaneous Nodules:
o Small, painless lumps (0.5–2 cm), mobile, and found over bony prominences (hands, feet, elbows,
occiput, occasionally vertebrae).
o Delayed manifestation, appearing 2–3 weeks after disease onset.
o Last a few days to 3 weeks and are commonly associated with carditis.

Other Features of ARF

• Fever:
o Present in most cases of ARF, but rare in pure chorea.
o High-grade fever (≥39°C) is typical, though lower-grade fever can also occur.
• Acute-Phase Reactants:
o Elevated in most

o
Evidence of a Preceding Group A Streptococcal Infection
• Essential for Diagnosis:
o Evidence of a preceding group A streptococcal infection is crucial for diagnosing ARF, except in cases
of chorea and low-grade carditis, which may appear months later.
• Serologic Testing:
o Most cases lack a positive throat swab culture or rapid antigen test, so serologic evidence is usually
required.
o Common tests include anti-streptolysin O (ASO) and anti-DNase B (ADB) titers.
• Age-Specific Reference Ranges:
o For accurate diagnosis, age-specific reference ranges should be established based on a local population of
healthy individuals without recent group A streptococcal infection
o cases, indicating inflammation.

Confirming the Diagnosis of ARF

• No Definitive Test:
o Diagnosis relies on a combination of clinical features, evidence of preceding group A streptococcal
infection, and the exclusion of other diagnoses.
• Jones Criteria:
o Developed by Dr. T. Duckett Jones in 1944 to aid diagnosis.
o The most recent revision includes low-risk criteria for populations with low ARF incidence and more
sensitive criteria for all other populations.

Confirming the Diagnosis of ARF

• No Definitive Test:
o Diagnosis relies on a combination of clinical features, evidence of preceding group A streptococcal
infection, and the exclusion of other diagnoses.
 • Jones Criteria:
o Developed by Dr. T. Duckett Jones in 1944 to aid diagnosis.
o The most recent revision includes low-risk criteria for populations with low ARF incidence and more
sensitive criteria for all other populations.
Treatment of Acute Rheumatic Fever (ARF)
• Diagnosis and Monitoring:
o Patients with possible ARF should be closely monitored for confirmation of diagnosis, heart failure
management, and initiation of secondary prophylaxis.
o Echocardiography should be performed for diagnosis and to assess the severity of carditis.
• Antibiotics:
o Penicillin is the drug of choice for treating the group A streptococcal infection:
▪ Oral: Phenoxymethyl penicillin (500 mg twice daily) or amoxicillin (50 mg/kg daily for 10 days).
▪ IM: Single dose of 1.2 million units of benzathine penicillin G.
• Salicylates and NSAIDs:
o Used for treating arthritis, arthralgia, and fever after diagnosis confirmation.
o Aspirin: 50–60 mg/kg per day (up to 100 mg/kg/day for severe cases).
o Naproxen: Alternative with a dose of 10–20 mg/kg per day, often preferred for safety and twice-daily
dosing.
o These medications are not proven effective for treating carditis or chorea.
o Salicylate toxicity (nausea, vomiting, tinnitus) may occur at higher doses, requiring dose reduction.
• Symptomatic Treatment:
o Treatment is largely symptomatic with no proven method to alter the development or severity of
rheumatic heart disease (RHD).
o Heart failure treatment may be life-saving in cases of severe carditis.

Management of Congestive Heart Failure (CHF) in ARF

• Glucocorticoids:
o The use of glucocorticoids in ARF remains controversial.
o Meta-analyses have shown no clear benefit in improving short- or long-term outcomes for carditis.
o Prednisone or prednisolone (1–2 mg/kg per day, max 80 mg) may be used for severe carditis with heart
failure, typically for a few days or up to 3 weeks.
o Benefits must be weighed against potential adverse effects.
• Management of Heart Failure:
o Detailed management strategies for heart failure can be found in Chapter 258.
• Bed Rest:
o Long-term bed rest is no longer widely recommended.
o Bed rest should be prescribed for arthritis, arthralgia, and heart failure as needed.
o Gradual mobilization is encouraged once symptoms are controlled.

Chorea Management in ARF

 • Medications:
o Medications do not affect the duration or outcome of chorea but can help control abnormal movements.
o Milder cases: Managed with a calm environment.
o Severe cases: Preferred medications include carbamazepine or sodium valproate, rather
than haloperidol.
o Response to medication may take 1–2 weeks; treatment should continue for 1–2 weeks after symptoms
subside.
• Corticosteroids:
o Recent evidence suggests corticosteroids may reduce symptoms more rapidly in severe or refractory
cases.
o Prednisone or prednisolone (0.5 mg/kg daily) can be used, with weaning as early as possible, ideally
after 1 week if symptoms improve.
o Slower weaning or dose escalation may be needed if symptoms worsen.

IVIG and Prognosis in ARF

• IVIG Use:
o Small studies suggest IV immunoglobulin (IVIg) may help resolve chorea more rapidly but show no
benefit for carditis in ARF without chorea.
o Due to limited evidence, IVIg is not recommended except in cases of severe, refractory chorea.
• Prognosis:
o Untreated ARF lasts around 12 weeks.
o With treatment, patients are usually discharged within 1–2 weeks.
o Inflammatory markers should be monitored every 1–2 weeks until normalized (usually 4–6 weeks).
o Echocardiography should be performed after 1 month to assess carditis progression.
o Patients with severe carditis require close long-term monitoring.
• Post-Acute Care:
o Long-term management focuses on secondary prophylaxis to prevent recurrence.
o Patients should be enrolled in an ARF registry (if available), and follow-up should be ensured
through primary care providers.
o Families should be educated on the importance of adherence to secondary prophylaxis.

Prevention of Acute Rheumatic Fever (ARF)

Primary Prevention
• Goal: Prevent group A streptococcal (GAS) infections, particularly throat infections, to reduce ARF risk.
• Strategies:
o Elimination of overcrowding in housing to reduce streptococcal transmission.
o Vaccine development efforts are underway, but no vaccine currently exists.
o Antibiotic treatment of sore throat (GAS pharyngitis) with penicillin within 9 days of onset can prevent
nearly all cases of ARF.
o In resource-poor regions where microbiologic diagnosis isn't feasible, clinical algorithms or blanket
treatment of all sore throats with penicillin is recommended, even if it leads to overtreatment.
o Prevention of skin infections like impetigo is important in areas where it's associated with ARF,
although antibiotic treatment for skin infections doesn't have proven efficacy in preventing ARF directly.
Secondary Prevention
• Goal: Prevent recurrent episodes of ARF and progression to rheumatic heart disease (RHD).
• Key Strategy: Long-term antibiotic prophylaxis with benzathine penicillin G.
o Dosage: 1.2 million units (600,000 units for children ≤27 kg) every 4 weeks. In high-risk cases, it may be
given every 2–3 weeks.
o Alternatives: Oral penicillin V (250 mg twice daily) or erythromycin (250 mg twice daily for penicillin-
allergic patients), though benzathine penicillin G is preferred.
• Duration of Prophylaxis:
o Depends on the time since the last ARF episode, age, and severity of RHD.
o Prophylaxis may continue for many years, especially for individuals with severe RHD or recurrent ARF.
• Registries: Implementation of ARF/RHD registries helps monitor patients, track adherence to prophylaxis, and
improve follow-up care.