Rheumatic fever: topic map

1. Definition, epidemiology, and risk factors
2. Causative organism and pathogenesis
   • Group A Streptococcus (GAS)
   • Molecular mimicry and autoimmune tissue injury
   • Why heart valves, joints, brain, and skin are affected
3. Pathology and rheumatic heart disease
4. Clinical features
   • Migratory polyarthritis, carditis, Sydenham chorea, erythema marginatum, subcutaneous nodules
5. Diagnosis
   • Revised Jones criteria, proof of preceding GAS infection, investigations, echocardiography
6. Differential diagnosis and complications
7. Acute treatment
   • Eradication of GAS, anti-inflammatory therapy, management of carditis/heart failure, chorea
8. Primary and secondary prevention
   • Treatment of streptococcal pharyngitis
   • Benzathine penicillin prophylaxis, schedules, and duration
9. Prognosis and exam-focused revision tables

High-yield overview

Acute Rheumatic Fever (ARF)

Definition

Etiology and risk factors

Causative agent

• GAS, especially rheumatogenic strains of Streptococcus pyogenes.
• ARF typically follows untreated or inadequately treated GAS pharyngitis after about 2-4 weeks.
• Certain endemic settings may associate superficial streptococcal skin infection with RF/RHD, but the classic relationship is with pharyngitis.

Risk factors

• Age 5-15 years
• Previous ARF, which markedly increases risk of recurrence
• Household overcrowding, poverty, poor sanitation
• Inadequate access to diagnosis and treatment of streptococcal throat infection
• Genetic susceptibility and family predisposition
• Living in an area with high prevalence of ARF/RHD

Pathogenesis

Central concept: molecular mimicry

Sequence

GAS pharyngitis
       ↓
Immune response against streptococcal M protein and other antigens
       ↓
Antibodies and T lymphocytes formed against GAS
       ↓
Cross-reaction with host proteins due to antigenic similarity
       ↓
Autoimmune inflammation of heart, joints, brain, skin, and subcutaneous tissue

Mechanism in detail

1. GAS infection of pharynx
   • Streptococcal M proteins are important virulence antigens.
   • A susceptible host produces antibodies and activated CD4+ T cells against these antigens.
2. Molecular mimicry
   • Some GAS epitopes resemble host proteins, including:
     • Cardiac myosin
     • Valve endothelium proteins
     • Laminin
     • Components in basal ganglia
3. Cross-reactive immune damage
   • Antibodies bind host tissue and activate inflammatory pathways.
   • T cells infiltrate the myocardium and valves.
   • Cytokines, macrophages, and cellular immune responses sustain tissue injury.
4. Resultant organ involvement
   • Heart: antibody binding and T-cell infiltration cause pancarditis and valvulitis.
   • Joints: immune-complex-related sterile inflammation causes migratory arthritis.
   • Basal ganglia: cross-reactive antibodies cause Sydenham chorea.
   • Skin: delayed hypersensitivity-mediated lesions cause erythema marginatum and nodules.

Important point

• ARF is a post-infectious immune disease.
• GAS cannot usually be cultured from the affected heart, joint, or brain.
• ARF itself is not contagious, but GAS pharyngitis is contagious.
• Only a small proportion of individuals with untreated GAS pharyngitis develop ARF.

Pathology

Cardiac pathology

1. Pericarditis
   • Fibrinous or serofibrinous pericarditis
   • May produce pericardial rub and chest pain
2. Myocarditis
   • Interstitial inflammatory infiltrate
   • May lead to cardiomegaly, tachycardia, arrhythmia, and heart failure
3. Endocarditis and valvulitis
   • The most clinically important lesion
   • Small sterile vegetations develop along the lines of valve closure
   • Usually affects the mitral valve, followed by the aortic valve
   • Acute disease commonly causes mitral regurgitation, with or without aortic regurgitation

Aschoff body

Components

• Central fibrinoid necrosis
• Surrounding lymphocytes and plasma cells
• Activated macrophages called Anitschkow cells
  • Have elongated, wavy, ribbon-like nuclei
  • Also called caterpillar cells
• Multinucleated giant cells may be present

Chronic rheumatic heart disease

Common chronic valvular lesions

• Mitral stenosis: most characteristic late lesion
• Mitral regurgitation
• Mixed mitral stenosis with regurgitation
• Aortic regurgitation or aortic stenosis
• Less commonly tricuspid involvement

Clinical features

1. Fever and constitutional symptoms

• Fever, malaise, fatigue, anorexia
• Usually begins 2-4 weeks after sore throat.
• Fever may be high with arthritis and carditis.

2. Migratory polyarthritis

• Commonly affects large joints:
  • Knees
  • Ankles
  • Elbows
  • Wrists
• Acute, painful, red, swollen joint
• Migratory: one joint improves as another becomes involved.
• Usually no permanent deformity or chronic joint damage.
• Rapid, dramatic improvement with aspirin or NSAIDs supports the diagnosis.

3. Carditis

• Most serious manifestation because it determines long-term prognosis.
• May be clinical or subclinical, detected only by echocardiography.
• Features:
  • Tachycardia out of proportion to fever
  • New mitral regurgitation murmur, usually apical pansystolic murmur
  • Aortic regurgitation, early diastolic murmur
  • Cardiomegaly
  • Pericardial friction rub
  • Heart failure
• Severe carditis may produce acute pulmonary edema or congestive cardiac failure.

4. Sydenham chorea

• Involuntary, purposeless, irregular, non-rhythmic movements of limbs, trunk, and face
• Muscle weakness, hypotonia, emotional lability, poor handwriting, clumsiness
• Movements disappear during sleep
• May occur months after GAS infection
• Can be the sole manifestation of ARF
• Usually resolves, but may persist or recur.

5. Erythema marginatum

• Rare but highly suggestive of ARF
• Non-pruritic, evanescent, blanching, pink macules or papules
• Serpiginous or annular advancing border with central clearing
• Mainly on trunk and proximal limbs
• Usually spares face
• More visible with warmth.

6. Subcutaneous nodules

• Small, firm, painless, freely mobile nodules
• Usually over extensor surfaces and bony prominences:
  • Elbows
  • Knees
  • Wrists
  • Occiput
  • Spine
• Often associated with severe carditis.

Diagnosis

Revised Jones criteria

• Two major criteria, or
• One major plus two minor criteria

• Two major, or
• One major plus two minor, or
• Three minor criteria,

Major criteria

Carditis

Minor criteria

Evidence of preceding GAS infection

• Positive throat culture for GAS
• Positive rapid antigen detection test
• Elevated or rising antistreptolysin O titre (ASO)
• Elevated anti-DNase B titre
• Recent scarlet fever

Exceptions

Investigations

1. CBC
   • Mild normocytic normochromic anemia
   • Leukocytosis may occur
2. Inflammatory markers
   • Raised ESR
   • Raised CRP
3. Evidence of GAS infection
   • Throat swab culture
   • Rapid antigen test
   • ASO titre
   • Anti-DNase B titre
4. ECG
   • Prolonged PR interval
   • May identify arrhythmia
5. Chest radiograph
   • Cardiomegaly
   • Pulmonary venous congestion or edema in heart failure
6. Echocardiography with Doppler
   • Essential to detect clinical or subclinical carditis
   • Detects mitral/aortic regurgitation, ventricular function, chamber enlargement, and pericardial effusion.

Differential diagnosis

Treatment

1. Eradicate residual GAS.
2. Control inflammation and relieve symptoms.
3. Identify and treat carditis, heart failure, and chorea.
4. Prevent recurrent ARF and progressive valvular injury.

1. General measures

• Admit if carditis, significant arthritis, severe chorea, diagnostic uncertainty, or social concerns.
• Bed rest during acute febrile illness and active carditis.
• Regular clinical examination, ESR/CRP, ECG, and echocardiographic follow-up.
• Dietary salt restriction if heart failure is present.

2. Eradication of GAS

Preferred regimens

3. Anti-inflammatory treatment

Arthritis

• Aspirin or another NSAID such as naproxen is used to relieve fever, pain, and arthritis.
• Response is often striking within 24-48 hours.
• Avoid aspirin in children with suspected influenza or varicella because of the risk of Reye syndrome.

Carditis

• NSAIDs may be used for symptomatic inflammation.
• Corticosteroids are sometimes used in severe carditis, especially with heart failure, but they have not conclusively been shown to prevent later rheumatic valvular disease.
• Therefore, steroid use should be individualized and supervised by a pediatrician/cardiologist.

4. Treatment of heart failure

• Bed rest and careful fluid balance
• Salt restriction
• Diuretics, such as furosemide
• ACE inhibitor when appropriate
• Digoxin selectively, usually with specialist input
• Treat severe acute valvular regurgitation in consultation with cardiology/cardiothoracic surgery.

5. Treatment of Sydenham chorea

Mild chorea

• Rest, reassurance, protection from injury
• School support and psychological support

Severe or disabling chorea

• Valproate or carbamazepine are commonly used.
• Haloperidol may be used in selected cases, but adverse effects must be monitored.
• Corticosteroids or immunomodulatory treatment may be considered in severe refractory cases under specialist care.

Prevention

A. Primordial prevention

• Reduce overcrowding
• Improve housing, nutrition, sanitation, and access to healthcare
• Improve recognition of sore throat and access to antibiotics

B. Primary prevention

C. Secondary prevention

First choice

• 600,000 units for children <27 kg
• 1.2 million units for those ≥27 kg
• In high-risk settings, 3-weekly injection schedules may be preferred.

• Oral penicillin V twice daily
• Sulfadiazine daily in suitable patients
• Macrolide in true penicillin allergy

Duration of secondary prophylaxis

Prognosis

• Arthritis, rash, and nodules usually resolve completely.
• Chorea usually resolves but may relapse.
• Prognosis mainly depends on severity of carditis and the occurrence of recurrent ARF.
• Recurrent episodes cause cumulative valve injury and increase the risk of chronic RHD.
• Early diagnosis, echocardiography, appropriate treatment, and strict adherence to secondary prophylaxis reduce morbidity.

Short conclusion