Rheumatic Fever - Complete Long Answer (Pathology MBBS)

Definition

Etiology and Epidemiology

• Causative organism: Group A beta-hemolytic Streptococcus pyogenes (specifically rheumatogenic strains)
• Inciting site: Pharyngeal infection (not skin infection)
• Age group: Most commonly affects children between 5 and 15 years; first attacks can occur in middle to later life
• Incidence: Only 0.3% to 3% of individuals who experience streptococcal pharyngitis develop RF, indicating genetic susceptibility
• Geographic distribution: Remains a major public health problem in low-resource countries and in crowded, economically depressed urban areas; declined markedly in developed nations due to improved sanitation and antibiotic use

Pathogenesis (Molecular Mimicry)

1. Initial infection: Group A streptococcus infects the pharynx and expresses M proteins (virulence factors on the bacterial surface)
2. Immune sensitization: The host generates antibodies and CD4+ T cells directed against streptococcal M proteins
3. Cross-reactivity: These antibodies and T cells cross-react with host cardiac antigens - pericardial, myocardial, or valvular proteins - because of structural similarity between streptococcal M protein epitopes and cardiac self-antigens
4. Tissue damage mechanism:
   • Antibody binding to cardiac antigens activates complement
   • Fc-receptor-bearing cells (neutrophils and macrophages) are recruited
   • CD4+ T cell cytokine production leads to macrophage activation (within Aschoff bodies)
   • Combined antibody-mediated and T cell-mediated reactions cause tissue injury
5. Key proof of immune basis: Streptococci are completely absent from the cardiac lesions
6. Delay: The 2-3 week latent period between infection and symptoms corresponds to the time needed to mount an adequate immune response
7. Genetic susceptibility: An intrinsic genetic factor predisposes a small subset of infected individuals to develop the cross-reactive immune response

Morphology (Pathological Changes)

1. Acute Rheumatic Fever - Pancarditis

A. Aschoff Bodies (PATHOGNOMONIC)

• Focal granulomatous lesions found in the myocardium (interstitium)
• Composition: Foci of T lymphocytes, occasional plasma cells, and activated macrophages
• Central zone: Area of fibrinoid necrosis (collagen surrounded by activated macrophages)
• Characteristic cells - Anitschkow cells (Anitschkow myocytes / Caterpillar cells):
  • Plump activated macrophages with abundant cytoplasm
  • Central round-to-ovoid nuclei, occasionally binucleate
  • Chromatin condenses into a central, slender, wavy ribbon = "caterpillar cells" or "owl-eye" nuclei
• Giant cells (Aschoff giant cells) may be present

Fig. 12.22 (B) from Robbins Pathologic Basis of Disease shows the microscopic appearance of an Aschoff body with characteristic Anitschkow cells (arrows).

Fig 12.22 - Acute and chronic rheumatic heart disease. (A) Acute mitral valvulitis with small verrucae along the line of closure (arrows). (B) Aschoff body in myocardium with Anitschkow cells (arrows). (C) "Fish-mouth" stenosis of mitral valve in chronic RHD. (D) Fused chordae tendineae. (E) Thickened, fused aortic valve cusps. - Robbins, Cotran & Kumar Pathologic Basis of Disease

B. Pericarditis

• Fibrinous or serofibrinous pericarditis - produces a "bread-and-butter" appearance on gross examination
• Usually resolves without significant sequelae

C. Myocarditis

• Diffuse inflammation with Aschoff bodies throughout the myocardial interstitium
• Can cause cardiac dilation leading to functional mitral valve insufficiency or heart failure
• Accounts for the 1-2% mortality in fulminant RF

D. Endocarditis (Valvulitis) - Most Clinically Significant

• Inflammation of the endocardium and left-sided valves
• Fibrinoid necrosis within the valve cusps or tendinous cords
• Verrucae: Small (1-2 mm), firm, warty vegetations overlying the necrotic foci
  • Located along the lines of valve closure
  • Single row arrangement
  • These are sterile, unlike infective endocarditis vegetations
• MacCallum plaques: Irregular thickenings on the posterior wall of the left atrium, caused by subendocardial lesions (exacerbated by regurgitant jet injury)

2. Chronic Rheumatic Heart Disease (RHD)

Mitral Valve (Most Commonly Affected)

• Affected in virtually 100% of cases of chronic RHD
• Isolated mitral involvement: ~two-thirds of cases
• Mitral + aortic involvement: ~25% of cases

1. Leaflet thickening - due to fibrosis and neovascularization
2. Commissural fusion - fusion of adjacent leaflet edges
3. Shortening of leaflets - overall reduction in valve area
4. Thickening and fusion of the chordae tendineae - cords become short, thick, and matted
5. "Fish-mouth" or "button-hole" stenosis - the classic appearance of severe mitral stenosis due to calcification and fibrous bridging across commissures
6. RHD is virtually the only cause of mitral stenosis

Consequences of Mitral Stenosis:

• Progressive left atrial dilation
• Mural thrombi in left atrium (risk of systemic embolism)
• Pulmonary hypertension - from chronic pulmonary venous congestion
• Pulmonary vascular and parenchymal changes
• Right ventricular hypertrophy (cor pulmonale)
• Left ventricle is largely unaffected in pure mitral stenosis

Aortic Valve

• Involved in ~25% of RHD cases (usually with mitral)
• Thickening and fusion of cusps, leading to aortic stenosis or regurgitation

Microscopy in Chronic RHD:

• Organization of acute inflammation
• Postinflammatory neovascularization
• Transmural fibrosis obliterating normal leaflet architecture
• Aschoff bodies are rarely seen in surgical/autopsy specimens from chronic RHD (due to the long intervals between acute episodes and chronic deformity)

Clinical Features

Major Jones Criteria (Revised)

Minor Jones Criteria

• Fever
• Arthralgia
• Elevated acute-phase reactants (ESR, CRP, leukocytosis)
• Prolonged PR interval on ECG
• Evidence of preceding streptococcal infection (elevated ASO titer, positive throat culture)

Diagnosis (Revised Jones Criteria, 2015)

• Evidence of preceding GABHS infection, PLUS
• 2 major manifestations, OR
• 1 major + 2 minor manifestations

Laboratory Findings

Comparison: Vegetative Endocarditis Forms (MBBS Exam Favourite)

Prognosis and Complications

1. Recurrence: After initial RF, there is increased vulnerability to reactivation with each subsequent streptococcal pharyngitis; damage is cumulative with each episode
2. Chronic RHD: Manifests years to decades after the initial attack
3. Complications of chronic RHD:
   • Cardiac murmurs (mitral stenosis = most common valve lesion)
   • Atrial fibrillation (especially with mitral stenosis)
   • Thromboembolic complications (stroke)
   • Infective endocarditis (superimposed on damaged valves)
   • Heart failure
4. Mortality: ~1-2% die from fulminant RF cardiac involvement in the acute phase

Prevention

Summary for Quick Recall

RF = GABHS pharyngitis → molecular mimicry → cross-reactive immunity
   → M protein antibodies attack cardiac antigens
   → PANCARDITIS:
        Pericarditis (bread-and-butter)
        Myocarditis (Aschoff bodies - Anitschkow/caterpillar cells)
        Endocarditis (small verrucae on line of closure, MacCallum plaques)
   → Repeated attacks → Chronic RHD
        Mitral stenosis ("fish-mouth") → LA dilation → AF → embolism
        Aschoff bodies = T cells + plasma cells + Anitschkow macrophages

• Aschoff body is pathognomonic of rheumatic carditis
• Anitschkow cells (caterpillar cells) are activated macrophages, not cardiomyocytes
• RHD is virtually the only cause of mitral stenosis
• Vegetations of RF are small, sterile, on the line of closure (unlike large, friable, destructive vegetations of infective endocarditis)
• Pathogenesis = molecular mimicry (cross-reactivity between M protein and cardiac antigens)
• Streptococci are absent from RF lesions (proving immune basis)
• MacCallum plaques = left atrial wall subendocardial lesions