M protein of rheumatogenic GAS has distinct structural characteristics that are akin to human heart tissue, particularly sarcolemmal membrane proteins and cardiac myosin. The major factors that lead to risk of ARF are the severity of the immune response to GAS pharyngitis and persistence of GAS organisms during convalescence. A very small proportion (0.3-3 per cent) of patients suffering from GAS throat infection ultimately develop ARF and this along with a familial predisposition of ARF points to a genetic susceptibility. However, in our Indian patients a genetic linkage to HLA DR3 in patients, with ARF has been demonstrated. For confirmation of the initial diagnosis of acute rheumatic fever, evidence of prior GAS infection is required. Several rapid GAS antigen tests are available. Majority of these tests has a high degree of specificity but low level of sensitivity in clinical practice.

However, it must be stressed that a negative test does not rule out the GAS infection in the throat. At the same time in presence of a positive antigen test and positive throat culture, it is difficult to distinguish between a recent infection which can be associated with ARF and chronic carrier of GAS infection with ARF. Elevated or rising ASO titres (> 250Todd units in adults and >333 Todd units in children) are more reliable evidence of recent GAS infection than a positive culture or positive rapid antigen test and such titres are also significant for diagnosis.