Acute rheumatic fever

Acute rheumatic fever (ARF) is an inflammatory sequela involving the heart, joints, skin, and central nervous system (CNS) that occurs two to four weeks after an untreated infection with group A Streptococcus (GAS). The pathogenic mechanisms that cause rheumatic fever are not completely understood, but molecular mimicry between streptococcal M protein and human cardiac myosin proteins is thought to play a role. Because of the structural similarities between the two proteins, antibodies and T cells activated to respond to streptococcal proteins also react with the human proteins, causing tissue injury and inflammation. In addition to nonspecific symptoms (e.g., fever, malaise, and fatigue), patients present with symptoms involving the heart (carditis or valvulitis), joints (migratory polyarthritis), skin (subcutaneous nodules, erythema marginatum), and/or CNS (Sydenham chorea). The diagnosis of ARF is primarily clinical and based on the Jones criteria. Diagnostic evaluation in ARF typically shows elevated inflammatory markers, positive antistreptococcal antibodies, and valvular damage on echocardiogram. The first-line treatment is penicillin combined with symptomatic anti-inflammatory treatment, typically with salicylates or glucocorticoids (if salicylates are not effective). ARF may be complicated by progressive, permanent damage to the heart valves (especially the mitral valve), resulting in chronic rheumatic heart disease. Preventing the cardiac complications of ARF is the main goal of both primary prophylaxis (i.e., antibiotic therapy for GAS pharyngitis) and secondary prophylaxis (antibiotic administration following an episode of ARF).

• Delayed inflammatory complication of group A β-hemolytic streptococcal pharyngitis that usually occurs within 2–4 weeks of acute infection ^[1]
• One of the nonsuppurative complications of GAS pharyngitis
• Rheumatic heart disease refers to two clinical entities:
  • Acute pancarditis as a sequela of GAS infection
  • Chronic cardiac valvular changes as a complication of acute rheumatic fever

• Peak incidence: 5–15 years of age ^[2]
• Prevalence: more common in resource-limited countries ^[3]

Epidemiological data refers to the US, unless otherwise specified.

• Previous infection with group A β-hemolytic streptococcus (GAS), also referred to as Streptococcus pyogenes
  • Usually acute tonsillitis or pharyngitis (“strep throat”)
  • GAS infections of the skin (e.g., erysipelas, impetigo, cellulitis) tend to be complicated by poststreptococcal glomerulonephritis rather than rheumatic fever.

• The exact pathogenesis is not yet entirely understood.
• Most commonly accepted mechanism involves the following: acute tonsillitis/pharyngitis caused by GAS without antibiotic treatment → development of antibodies against streptococcal M protein → cross-reaction of antibodies with nerve and myocardial proteins (most commonly myosins) due to molecular mimicry → type II hypersensitivity reaction → acute inflammatory sequela ^[2][4]

• Myocardial findings ^[5][6]
  • Aschoff bodies
    • Granuloma of rheumatic inflammation
    • Central area of fibrinoid necrosis
    • Surrounded by characteristic multinucleated giant cells (Aschoff cells) and other inflammatory cells (mononuclear cells, plasma cells, and T lymphocytes) due to a type IV hypersensitivity reaction.
  • Anitschkow cells
    • Cardiac histiocytes (mononuclear cells) appearing in Aschoff bodies
    • Large and elongated cells
    • Longitudinal section: ovoid nucleus containing wavy, caterpillar-like bar of chromatin (caterpillar cell)
    • Transverse section: owl-eye appearance

• Constitutional symptoms: : fever, malaise, fatigue
• Joints: migratory polyarthritis
• Heart
  • Pancarditis (endocarditis, myocarditis, and pericarditis)
  • Valvular lesions: most commonly on high-pressure valves
    • Mitral valve (∼ 65% of cases)
      • Early mitral regurgitation or prolapse
      • Late mitral stenosis: Rheumatic fever is the most frequent cause of mitral stenosis.
      • Mixed mitral stenosis/regurgitation
    • Aortic valve (∼ 25% of cases)
      • Aortic regurgitation
      • Aortic stenosis (late manifestation)
    • Tricuspid valve (∼ 10% of cases)
  • Dilated cardiomyopathy due to severe valvular disease, myocarditis
• CNS: Sydenham chorea (involuntary, irregular, nonrepetitive movements of the limbs, neck, head, and/or face) ^[7]
  • ♀ > ♂ (∼ 2:1)
  • Most common cause of acute chorea in children in the US ^[8]
  • Occurs 1–8 months after the inciting infection ^[9]
  • Clinical features
    • Sometimes asymmetrical or confined to one side (hemichorea)
    • Additional motor symptoms (e.g., ballismus, muscle weakness) and speech disorders (slurred or “jerky” speech)
      • Milkmaid grip: characterized by the inability to maintain muscle contraction in the hands → intermittent loss of contraction results in alternating squeeze and release of grip ("milking")
      • Choreic hand: characterized by intermittent wrist flexion with extension of the digits (“spooning” of the hand)
    • Neuropsychiatric symptoms (e.g., inappropriate laughing/crying, agitation, anxiety, apathy, obsessive-compulsive behavior)
  • Pathophysiology: Streptococcal antigens lead to antibody production → antibodies cross-react with structures of the basal ganglia (particularly the striatum) and cortical structures → reversible dysfunction of cortical and striatal circuits
• Skin
  • Subcutaneous nodules
  • Erythema marginatum: centrifugally expanding pink or light red rash with a well-defined outer border and central clearing.
    • Painless and nonpruritic
    • Location: The trunk and limbs are affected; the face is spared. May rapidly appear and disappear at different locations. ^[1]
    • Differential diagnosis: For details, see “Overview of annular skin lesions.”

Rheumatic heart disease tends to involve the high-pressure valves (i.e., the mitral and aortic valves).

Valvular lesions sometimes do not manifest until pregnancy, when blood volume is increased. ^[10]

The symptoms of acute rheumatic fever can be remembered by reading the JONES criteria (see “Diagnostics” below) as an acronym that replaces the “o” with a heart: J = Joints, ♥ = Pancarditis, N = Nodules, E = Erythema marginatum, S = Sydenham chorea

Approach ^[11][12]

• Patients should be evaluated for evidence of a preceding GAS infection via throat culture, antigen, or antibody test.
• ARF is diagnosed using the revised Jones criteria.
• All patients with suspected or confirmed ARF require a cardiac workup.

Revised Jones criteria ^[11][12]

• Diagnostic criteria for patients with laboratory findings of a preceding GAS infection
  • Initial episode of ARF: two major criteria or one major plus two minor criteria
  • Recurrent ARF: either the same as for an initial episode of ARF or the presence of three minor criteria

Routine laboratory studies ^[11]

Initial laboratory findings typically show nonspecific signs of infection.

• Complete blood cell count ^[11][13]
  • Typically shows leukocytosis
  • May show normochromic, normocytic anemia of chronic inflammation
• Acute phase reactants ^[11]
  • CRP: elevated, typically ≥ 30 mg/L
  • ESR: elevated, typically ≥ 60 mm/hour

Confirmation of GAS infection ^[11]

• Used to rule out differential diagnoses
• Any of the following test results can confirm recent GAS infection:
  • Tests showing elevated or rising antibodies
    • ↑ Antistreptolysin O titer (ASO)
    • ↑ Antistreptococcal DNAse B titer (ADB)
  • Positive throat culture
  • Positive rapid GAS carbohydrate antigen detection test
• False positives are possible due to colonization of GAS in the upper respiratory tract.
• For more information on the diagnosis of GAS pharyngitis, see "Acute tonsillitis."

Assessment for cardiac involvement ^[11][14][15]

• All patients with confirmed or suspected rheumatic fever require an ECG and echocardiography.

Assessment for neurological involvement ^[17][18]

• The diagnosis of Sydenham chorea is based on clinical and laboratory findings.
• Neuroimaging (MRI or CT brain)
  • Not routinely indicated but may be performed to exclude other forms of chorea
  • Findings are nonspecific and variable.
• Lumbar puncture: not routinely indicated; may be performed to exclude other disorders
• Echocardiography should be obtained in all patients with Sydenham chorea because concurrent cardiac involvement is common. ^[14]

Treatment of ARF involves pain relief for arthritis, antibiotics to both treat acute GAS infection and prevent recurrence, and medical management of associated complications.

GAS eradication ^[14]

• First-line: penicillin V
• In patients with penicillin allergy, use:
  • Cephalosporins (hypersensitivity without anaphylaxis)
  • OR macrolides (severe hypersensitivity to beta-lactam antibiotics) ^[14]
  • For dosages, see “Recommended antibiotic regimens for acute GAS pharyngitis.”

Symptomatic treatment of arthritis and fever

• First-line: nonsteroidal anti-inflammatory drugs (NSAIDs) ^[12][19]
  • Aspirin
  • Naproxen
• Second-line: glucocorticoids, e.g., prednisone

Cardiac involvement

Sydenham chorea ^[14][19]

In the majority of cases, Sydenham chorea is self-limiting, with most patients seeing an improvement within a few weeks and nearly all patients fully recovered by six months.

• Supportive therapy: indicated for all patients; may be the only treatment required in mild disease
  • Rest in a calm environment
  • Avoidance of overstimulation
  • Patient and caregiver education about the condition
• Pharmacotherapy
  • Consider for patients with difficulties performing activities of daily living.
  • Options include carbamazepine and valproic acid. ^[12][20]
  • Additional treatment options for patients with persistent symptoms or refractory severe disease include:
    • Prednisone
    • Risperidone
    • IVIG
    • Plasmapheresis

Primary prevention ^[21]

• Aims to prevent ARF from developing as a result of GAS infection
• Patients should receive prompt antibiotic treatment for GAS tonsillopharyngitis (e.g., with penicillin V) and streptococcal skin infections. ^[19]

Secondary prevention

• Patients with a history of ARF are at high risk for recurrence, which may worsen existing rheumatic heart disease.
• All patients require antibiotic prophylaxis.
  • Start immediately after completion of antibiotics for ARF.
  • Drug of choice: IM penicillin G benzathine every 4 weeks
  • Alternatively: oral penicillin V ^[14]
  • Patients with penicillin allergy: sulfadiazine
  • Antibiotic prophylaxis should be decided according to whichever of the following results in the longest treatment duration: ^[21]
    • Possible ARF: 12 months ^[14]
    • Rheumatic fever without carditis: 5 years or until the patient reaches 21 years of age
    • Rheumatic fever with carditis (with no residual heart disease): 10 years or until the patient reaches 21 years of age
    • Rheumatic fever with carditis and permanent valvular heart defects: 10 years or until the patient reaches 40 years of age
• Educate patients on early recognition of symptoms and the importance of adhering to prophylaxis.
• Emphasize the importance of dental care and regular dental checkups.

• Cardiac involvement is the most important prognostic factor.
  • Early death from rheumatic fever is usually due to myocarditis rather than valvular defects.
  • Patients with a history of carditis (and possible post-inflammatory scarring and calcification) during an initial rheumatic fever episode are at high risk of developing valvular heart defects with recurrent episodes → rheumatic heart disease