POST-STREPTOCOCCAL SEQUELAE

After one to three weeks following untreated Group A streptococcal infection, 1-3% of individuals develop non-suppurative post-streptococcal sequelae namely Acute Rheumatic Fever (ARF) or Acute Glomerulonephritis (AGN). By the time patients develop these sequelae, the primary infection would no longer be detectable. Both of these are considered to be hypersensitivity to streptococcal antigens and resultant autoimmune damage. 

Cross-reacting antigens of Streptococci:
      1. Capsular hyaluronic acid cross-reacts with human synovial fluid
      2. Cell wall protein (M protein) cross-reacts with myocardium
      3. Group A carbohydrate cross-reacts with cardiac valves
      4. Cytoplasmic membrane antigens cross-reacts with vascular intima

RHEUMATIC FEVER:
Pathogenesis: ARF usually follows repeated attacks of streptococcal pharyngitis by certain "rheumatogenic strains" of Streptococcus pyogenes (serotypes 1, 3, 5, 6 and 18). These strains usually produce large amounts of M protein and possess hyaluronic acid capsule. Because of cross-reaction of streptococcal antigens with human tissues, anti-streptococcal antibodies produced by patients react with self-tissues and damage them. ARF, which is usually seen in children 6-15 years of age, is characterized by inflammatory lesions involving heart, joints and sub-cutaneous tissue. Involvement of heart in acute stage may lead to death or rheumatic heart disease, which can proceed chronically leading to heart damage and later heart failure.

Patients are diagnosed for ARF if they meet at least two major manifestations or one major and two minor manifestations according to revised Jones criteria.
Major manifestations: carditis, polyarthritis, chorea, erythema marginatum and subcutaneous nodules (Aschoff nodules)
Minor manifestations: arthralgia, fever, elevated CRP levels, prolonged P-R interval by ECG and serological evidence of preceding streptococcal pharyngitis. 

Serological diagnosis: Retrospective evidence of streptococcal infection can be made by detection of anti-streptolysin O antibodies in patient serum. Commonly employed test is a latex slide agglutination test where latex particles coated with streptolysin O antigens are made to react with patient serum. A titre of 200 IU or more is suggestive of past streptococcal infection.

Prevention: Treating patients with antibiotics (e.g.Penicillin) within 9 days of onset of streptococcal pharyngitis can prevent ARF. Since recurrences are common, a life-long antibiotic prophylaxis is recommended in some cases following a single episode.

ACUTE GLOMERULONEPHRITIS:

Pathogenesis: While ARF follows upper respiratory tract infections, AGN can follow either pharyngitis or cutaneous infections. The disease typically occurs 6-10 days after onset of pharyngitis or 14-21 days after cutaneous infection. Serotypes 1, 4, 6, 12 and 25 are associated with pharyngitis-associated disease, whereas serotypes 2, 49, 53, 55, 56, 57 and 60 predominate in pyoderma-associated disease. These strains are referred as "nephritogenic strains". The AGN may result from cross-reaction between some streptococcal antigen and glomerular antigen. Recent evidence suggests that streptococcal antigens react with specific antibodies in the body and form immune complexes, which get deposited on the glomerular basement membrane. This initiates complement-mediated damage of the membrane (type III hypersensitivity). AGN is an acute inflammatory disease of renal glomeruli, characterized by hematuria, albuminuria and low levels of serum complement. It is self-limiting and resolves without any permanent damage. Recurrences are uncommon, and prophylaxis following an initial attack is unnecessary.

Serological diagnosis: Since antibodies against streptolysin O are either very low or not formed following pyoderma, ASO test is not useful in the retrospective diagnosis of AGN. Instead, anti-streptodornase B (anti-Dnase B) and anti-hyaluronidase are useful. A titre of 300 U or more for anti-streptodornase is significant.

Streptozyme test: This is a passive slide hemagglutination test, where erythrocytes are coated with crude extracts of extracellular antigens of streptococci. Patient's serum is mixed with coated erythrocytes and hemagglutination is considered positive. This test is positive following both pharyngitis and pyoderma infections.

Comparison of ARF and AGN: