Epidemiology

• Group A beta hemolytic Streptococcus (GABHS) is also called Streptococcus pyogenes.
• Globally, around 15 million people develop rheumatic fever (RF) or rheumatic heart disease (RHD) annually.
• Only pharyngitis leads to RF.
• RF is uncommon below age 5 years.
• RF recurrence is uncommon above age 34 years.
• 0.3 to 3% of untreated GABHS pharyngitis leads to RF.
• With past history of RF, 50% of untreated GABHS pharyngitis leads to RF.
• After RF, MS and post-pubertal chorea are more likely to develop in females.
• GABHS carrier state (no symptoms or antibodies) will not cause RF.
• Preceding pharyngitis is reported differently in different studies – from in most cases to in 30% cases only.
• The decline in incidence of RF began even before the development of penicillin and accelerated with penicillin introduction.

Pathophysiology

• M-protein
  • Surface molecule on GABHS
  • More than 100 subtypes.
  • Some subtypes make the strains mucoid- these can adhere better to the pharynx and are more rheumatogenic.
  • Antiphagocytic- persist in tissues for upto 2 weeks- leads to antibody production.
• Rheumatogenic strains produce serum opacity factor while glomerulonephritis producing strains do not.
• Antibodies-
  • Produced against M protein and N-acetyl glucosamine.
  • Cross-react against
    • Heart valves- laminin
    • Myocardium- myosin and tropomyosin
    • Skin- keratin
    • Synovium- vimentin
    • Subthalamic and caudate nuclei- lysogangliosides.
• The B cell alloantigen D8/17 predisposes to RF.

Pathology

• First few weeks- exudative phase
  • Valves-
    • Verrucous vegetations
    • Edematous inflammation with lymphocytes and macrohages.
    • Fibrinoid degeneration of collagen

1 to 6 months- proliferative phase

• Aschoff bodies-
  • Granulomas
  • Pathognomonic for rheumatic carditis
  • May occur earlier- at 2 weeks
  • May persist chronically without ongoing carditis

Evaluation

Timing

• Within first month-
  • Carditis
  • Arthritis
  • Erythema marginatum
• After first month-
  • Subcutaneous nodules
  • Chorea

Jones criteria

• Introduced in 1944
• In 1992, the guidelines changed to diagnosis of first attack of RF only.
• A diagnosis of RF can be made if-
  • Essential + 2 major
  • Essential + 1 major + 2 minor
  • Essential + RHD + 2 minor
  • Chorea
  • Low-grade carditis (insidious onset carditis)
• Jones and WHO criteria have being criticized as being poorly sensitive.
• If RF occurs for first time in adulthood-
  • Arthritis dominates, carditis is less common and other manifestations are rare.
  • Jones criteria become less specific.

Carditis

• 40 to 60 % of RF causes carditis.
• MR-
  • More common than AR
  • Myocarditis or pericarditis will not occur without valvulitis.
  • Soft, blowing PSM conducted to axilla.
  • S3 does not indicate severe MR as it can occur normally in children.
  • Carey Coombs murmur occurs in severe MR due to flow. Turbulence due to valvulitis also contributes.
  • Severe MR can cause heart failure.
  • Those with severe MR are more likely to get RHD subsequently.
  • Echo is more sensitive but less specific.
  • Echo features suggestive of pathological MR are-
    • Posterior direction
    • Holosystolic flow
    • Significant turbulence
    • Visualization in orthogonal planes
    • Echo shows valve nodularity in 25%.
    • Valvulitis extends into submitral apparatus in a significant percentage.
    • Chordal rupture can occur.
• AR-
  • Seen only along with MR.
  • A2 is still loud as valve mobility is not affected.
• Myocarditis-
  • Heart failure is more likely to be due to MR than due to myocarditis.
  • PR interval may be prolonged.
  • If LV function is preserved, troponin is not elevated.
  • RWMA of inferobasal segment may occur.
• Pericarditis-
  • Rub present.
  • Effusion may occur.
  • Does not cause tamponade or constriction.
• Subclinical carditis-
  • Can lead to chronic sequelae.
• Silent carditis-
  • Clinically silent, but echo abnormal.
  • Also called echocarditis.
  • Importance is controversial.
• Recurrent carditis –
  • RF in a known case of RHD.
  • Also called mimetic carditis.
  • DD is infective endocarditis.

Arthritis

• Most frequent manifestation- 75%.
• Earliest manifestation- within 2 to 3 weeks.
• Only manifestation in one-third to half.
• Very painful.
• Each joint is affected for 1 to 2 weeks.
• Total duration of polyarthritis is 1 month.
• Usually no chronic sequel. Rarely Jaccoud arthropathy, a non-specific pericarticular fibrosis.
• Arthritis and carditis are inversely related in severity.
• Salicylates may cause arthritis to be mono instead of poly.
• Failure to respond to salicylates goes against RF as the cause of arthritis.
• Large limb joints are affected.
• Post streptococcal reactive arthritis
  • Early after pharyngitis
  • ASO is positive.
  • Small joints of upper limbs
  • Less responsive to salicylates
  • Lasts for longer period than RF
  • Other manifestations of RF are absent
  • Patients can develop RHD
  • Secondary prophylaxis is recommended.

Chorea

• Also called Sydenham chorea
• Neurological features
  • Spooning with external rotation of hands
  • Fibrillatory tongue movements
  • Absence of chorea with sleep
• ASO and ESR/CRP will be normal.
• Incidence is 5 to 35%
• Presents at 1 to 7 months
• May last for months or years
• Recurrence is common.
• Chance of chronic cardiac squeals is more than 50%.
• Can cause psychiatric disturbances after decades.
• Other neurological problems in RF are-
  • Emotional lability
  • Obsessive compulsive behavior
  • Seizures
  • Migraine
• DD of RF associated neurological disease is PANDAS
  • Pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections
  • Occurs after Streptococcal infection
  • Not related to RF.

Cutaneous manifestations

• Erythema marginatum and subcutaneous nodules
• Both occur in single digit percentages only
• Subcutaneous nodules appear after many weeks, but resolves within 2 months. Erythema marginatum is an early manifestation, but may last for months or years.
• Subcutaneous nodules are firm and occur over major joints and bony prominences.
• Erythema marginatum occurs over trunk and proximal extremities.

Laboratory findings

• ESR and CRP
  • Parallel disease activity
  • ESR is affected by anemia and heart failure while CRP is not.
• ECG-
  • Tachycardia due to fever, pericarditis or myocarditis
  • Conduction disturbances
    • In 30%
    • Usually first degree heart block, rarely second or third degree
    • Does not predict chronic sequels
    • Prognostically  unimportant
    • QT prolongation is frequent, TDP is rare
    • Sudden death rarely
• Demonstration of antecedent Strep infection
  • Methods
    • Throat culture
    • Streptococcal antigen testing
    • Elevated or rising Streptococcal antibodies
  • Throat culture
    • False positive in carriers
    • False negative if antibiotic treatment
  • Streptococcal antigen tests
    • Specific, but low sensitivity
  • Streptococcal antibody tests
    • Rising level is more specific than elevated level
    • Elevated in non-GABHS infections also
    • Anti streptolysin O, anti deoxyribonuclease B, anti hyaluronidase and streptozyme
    • Rises in first month, plateaus for 3 to 6 months and returns to normal within one year.

Treatment

• General
  • Bed rest is not needed.
  • Anti-inflammatory agents (salicylates and steoids) do not influence the natural history.
• Eradication of GABHS from the throat
  • Effective antibiotic therapy within 10 days of pharyngitis eliminates the risk of RF.
  • GABHS is always penicillin sensitive.
  • Benzathine Pn is the best as compliance is not an issue.
  • Benzathine Pn 1.2 MU IM once, Penicillin V 500 mg bid for 10 days, amoxicillin 500 mg tds for 10 days, cephalosporins for 10 days or erythromycin for 10 days.
  • For penicillin allergy, erythromycin is recommended.
• Carditis
  • There is no role for salicylates, except for pericarditis.
  • Treated with steroids, though the utility is contested.
  • If valvular regurgitation leads to heart failure that cannot be medically controlled, valve sugery is needed. There is a higher than normal incidence of failed repair, morbidity and mortality.
• Arthritis
  • Salicylates are used. NSAIDs are alternatives.
  • Steroids are not given as the DD is infectious arthritis.
  • Aspirin 100 mg/kg/day in four or more divided doses.
  • Therapeutic blood level is 15 to 30 mg/dl.
  • Failure of pain to resolve within 24 hours suggests alternative diagnosis.
  • Monitor for GI side effects and tinnitus.
• Follow-up
  • Even if RF manifestations are mild, patient needs to be monitored long term for chronic sequels.
  • Benzathine Pn 1.2 MU IM every 4 weeks is the best regimen for secondary prevention of GABHS infection. If the chance of getting reinfected is thought to be high it is better given every 3 weeks.
  • Benzathine Pn is best as compliance is better.
  • Alternatives (oral)-
    • Penicillin V 250 mg bid
    • Erythromycin 250 mg bid
    • Sulfonamides 1 gm daily
  • Duration of prophylaxis-
  • No carditis- 5 years or age 18 (take whichever is longer)
  • Mild or healed carditis- 10 years or age 25 (take whichever is longer)
  • Moderate or severe carditis- Life long