Rheumatic Fever

Overview

Definition

Acute rheumatic fever (ARF) is an autoimmune condition that develops as a complication of streptococcal infection.

Epidemiology

• More common in children and adolescents (ages 5–15)
• Worldwide prevalence: approximately 33.4 million
• Incidence: 19 cases per 100,000 school-age children worldwide
• Incidence: < 2 per 100,000 children in developed countries
• The incidence is higher in socioeconomically deprived areas.

Etiology

• Recent group A β-hemolytic streptococci (GAS)/Streptococcus pyogenes infection: 
  • Almost exclusively pharyngitis or tonsillitis
  • Associated with strains that are heavily encapsulated and rich in M protein
• Genetic predisposition

Pathophysiology

The pathogenesis is not completely understood.

Genetic predisposition is likely, as rheumatic fever tends to be familial:

• Associated with the class 2 HLA antigens DR2 and DR4
• HLA-B5
• Polymorphisms of transforming growth factor beta (TGF-𝛃) and interleukin-1 (IL-1)

The major implied mechanism is molecular mimicry:

• Humoral and cellular response to streptococcal antigens as a result of infection
• Cross-reaction with human proteins that share some structural similarity with bacterial antigens

Acute phase

• Immune response caused by molecular mimicry between the M protein of GAS and the carbohydrate antigens on human cardiac myosin and laminin
• Binding of cross-reactive antibodies at the valve surface activates CD4 T cells and B lymphocytes:
  • T helper and cytokines mediate local tissue damage.
  • Aschoff bodies: rheumatic granulomas
  • Pancarditis and pericardial exudates decrease ventricular filling capacity and can cause congestive heart failure.
• Antibodies against GAS carbohydrate antigen cross-react with neuronal cells in the basal ganglia → release excess dopamine → chorea manifestations
• Joint tissue destruction → arthritis/arthralgia

Chronic phase

• Mostly affects the heart
• Inflammation leads to neovascularization and healing by fibrosis.
• Buildup of fibrotic tissue in heart valves
• Stenosis of heart valves

Clinical Presentation

Clinical diagnostic criteria

• ARF typically presents 2–4 weeks after streptococcal pharyngitis.
• Clinical manifestations of ARF are known as Jones criteria.
• Major manifestations:
  • Arthritis (60%–80%)
  • Carditis/valvulitis (50%–80%)
  • Sydenham chorea (10%–30%)
  • Subcutaneous nodules(< 10%) 
  • Erythema marginatum (< 6%)
• Minor manifestations:
  • Arthralgia
  • Fever
  • Elevated acute-phase reactants:
    • ESR
    • CRP
  • Prolonged PR interval on electrocardiography

Major symptoms

• ARF arthritis:
  • Migratory polyarthritis 
  • Affects the larger joints
  • Commonly seen in knees, ankles, elbows, and wrists
• Rheumatic heart disease:
  • Typically pancarditis: endocarditis, myocarditis, and pericarditis 
  • Endocarditis is usually the most prominent manifestation.
  • Most commonly affects mitral valve (65% of cases):
    • Mitral regurgitation or prolapse is an early sign.
    • Mitral stenosis is a late sign (chronic).
  • Patients may have shortness of breath, dyspnea on exertion, chest pain, or orthopnea, depending on severity.
  • Endocarditis and myocarditis can lead to dilated cardiomyopathy (10% of cases).
• Sydenham chorea:
  • Purposeless, involuntary, nonstereotypical movements  
  • Affects the trunk and extremities 
  • Often presents with associated muscle weakness and emotional lability
• Subcutaneous nodules: 
  • Firm, painless protuberances found on extensor surfaces 
  • Affect the knees, elbows, and wrists
• Erythema marginatum:
  • Unique, evanescent, pink rash
  • Pale center and rounded or serpiginous margins 
  • Typically on trunk and proximal extremities (spares the face)

Mnemonic

To recall the main clinical manifestations in acute rheumatic fever, remember the Jones criteria (written as J❤NES):

• Joints (migratory polyarthritis)
• ❤ (carditis)
• Nodules (subcutaneous)
• Erythema marginatum
• Sydenham chorea

Diagnosis

Diagnostic criteria

• Evidence of preceding GAS infection
• Initial episode:
  • 2 major manifestations
  • 1 major + 2 minor manifestations
• Recurrent episode: 
  • 2 major manifestations
  • 1 major + 2 minor manifestations
  • 3 minor manifestations
• Exceptions to the above criteria:
  • Chorea as the only manifestation
  • Indolent carditis as the only manifestation becoming evident months after acute infection

Laboratory studies

• Evidence of streptococcal infection:
  • Throat culture: negative in 75% of cases by the time ARF develops 
  • Streptococcal antigen test: commonly negative by the time of ARF presentation
  • Antibody titers (most helpful for ARF diagnosis):
    • Antistreptolysin O (ASO)
    • Antideoxyribonuclease B (ADB)
    • Antistreptokinase
    • Antihyaluronidase
• Other findings:
  • Leukocytosis
  • Anemia
  • ↑ CRP
  • ↑ ESR

Imaging

• Echocardiography with Doppler: 
  • Required in all cases of confirmed and suspected RF
  • Carditis
  • Valvular vegetations
  • Mitral and/or aortic regurgitation (acute phase)
  • Mitral stenosis (chronic phase)
• Chest X-ray:
  • Cardiomegaly
  • Pulmonary edema in patients in whom heart failure has developed

Management

Treatment

Goals:

• Eradication of streptococci and bacterial antigens from the pharyngeal region
• Supportive/symptomatic treatment for arthritis, carditis, and chorea
• Prevention of cardiac complications

Eradication of streptococcal infection:

• Penicillin is the drug of choice.
• Amoxicillin is used if penicillin is not available.
• Cephalosporins are another option.

Arthritis:

• Aspirin
• Nonsteroidal anti-inflammatory drugs (NSAIDs): ibuprofen, naproxen

Severe carditis:

• Corticosteroids
• Bed rest
• Heart failure medications:
  • Diuretics 
  • Vasodilators such as nitroglycerin can reduce strain on the heart.
  • Digoxin
• Monitoring and treating for arrhythmias caused by myocarditis
• Surgery is not performed in the acute phase except for emergent indications:
  • Valve leaflet rupture
  • Chordae tendineae rupture
• Surgical repair may be required in the chronic phase for mitral stenosis.

Sydenham chorea is usually self-limited and does not require specific treatment.

Prevention

• Primary: prompt antibiotic treatment of streptococcal pharyngitis
• Secondary:
  • Intramuscular penicillin G benzathine is widely used to prevent recurrence.
  • Administered every 28 days
  • In patients with a penicillin allergy, oral macrolides are an alternative.
  • Initiated after treatment for original infection ends
  • Duration of prophylaxis depends on original presentation and severity.

Prognosis

• Carditis will resolve without sequelae in 65%–75% of patients.
• 90% of acute episodes last < 3 months.
• Risk of recurrence is greatest within the first year.

Differential Diagnosis

• Bacterial sepsis: a life-threatening syndrome that occurs when a bacterial pathogen and its products move from the infection source into the bloodstream. Pneumonia is the most common known precipitating event. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Management is based on the cause and includes treatment with antibiotics.
• Kawasaki disease: a febrile vasculitic syndrome of early childhood characterized by vasculitis of medium-sized arteries. Kawasaki disease is also known as infantile polyarteritis nodosa and mucocutaneous lymph node syndrome. Multiple systems are involved, but the most serious is involvement of the coronary arteries. Management involves intravenous immunoglobulin and high-dose aspirin. 
• Septic arthritis: refers to the invasion of the joint space by microorganisms such as bacteria, viruses, and fungi. Septic arthritis can be caused by a variety of organisms, with the most common being Staphylococcus aureus. Orthopedic procedures are a common cause of S. aureus infection. Cultures from joint aspiration are diagnostic, with antibiotic therapy tailored to the specific organism found. Antibiotic treatment is aimed at the causative agent. 
• Systemic lupus erythematosus (SLE): an autoimmune disorder characterized by the production of antibodies against nuclear and cytoplasmic antigens, multisystem inflammation, and protean clinical manifestations. Symptoms include malar rash, joint pain, fever, proteinuria, hypertension, anemia, lymphopenia, seizures, and/or psychosis. Management includes topical steroids, IV steroids, or methotrexate. 
• Infective endocarditis: a condition characterized by inflammation of the inner lining of the heart and valves caused by infection. Diagnosis is made with echocardiography, and management is based on treatment of the causative agent. 
• Lyme disease: a zoonotic infection caused by Borrelia burgdorferi, which presents initially with a localized rash and ultimately causes systemic infection involving the joints, skin, and nervous system. Neurologic, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis relies on clinical findings and a tick exposure and is supported by serologic testing. Antibiotics are used for treatment. 
• Rheumatoid arthritis: a chronic inflammatory autoimmune disorder characterized by pain, swelling, and destruction of synovial joints. The main symptoms on presentation are morning stiffness and swelling of small joints of the hand. Diagnosis is based on a strong clinical suspicion and confirmed by the presence of serologic markers and acute-phase reactants. Treatment involves NSAIDs and immunosuppressive medications.