Rheumatic Fever is an abnormal, delayed, often-recurrent probably autoimmune reaction to Group A b hemolytic streptococcal pharyngitis involving joints, skin, brain, serous surfaces and heart valves.If it would not have involved valves, the disease would have been of little practical consequence.Whatever be the theory of its pathogenesis, few facts has not been explained by any of the theories:
- It is predominantly but not exclusively, a disease of socially and economically disadvantaged population.
- It is a sequelae of post-streptococcal (beta hemolytic) pharyngitis and occurs only in 3% of infected individuals.
- It does not follow non-pharyngeal streptococcal infection.
- It is virtually unknown in infants before 2nd birthday and rare is small children.
- There has been a familial tendency.
The relative decrease in the incidence of acute rheumatic fever and its cardiac sequelae in the western world have led many of the young physicians in the west to consider the disease "as a thing of the past". But it is somewhat erroneous since even in United States and Western Europe, rheumatic fever maintains its position as one of the leading cause of acquired heart disease in children. Amongst the world population from developing countries, rheumatic fever can be looked upon as a devastating public health problem. The recent decline of morbidity and mortality from the disease in the west commenced before the event of antibiotics, possibly because of improvement in socioeconomic conditions or other unknown factors. In the developing world where socioeconomic are far from being ideal, one is obliged taking a critical look at rheumatic fever. It is equally important to maintain an equal curious eye on the disease in the west since the return of the disease may again occur in the west if resistance to penicillin appears amongst streptococci or if other unknown factors prevail.
It is with this thought in mind that despite the present discrepancies in incidence, prevalence, morbidity and mortality of the disease in different parts of the world, physicians everywhere must remember the memorable quotations of Dr. T. B. Jones, "The exact incidence of the disease or the decrease in the incidence or in severity, seems of less importance than the need to gain further knowledge of how and why human beings develop rheumatic fever. So long as surgeons find mitral valve stenosis requiring valvotomy or children continue to die of rheumatic fever and rheumatic heart disease, the problem exists. Rheumatic fever is and will remain with us until new knowledge and better preventive or therapeutic agents become available".
This brief review deals with the pathogenesis of the disease and a few new thoughts are introduced.
Pathogenesis of Rheumatic FeverFor rheumatic fever to develop there are at least
four absolute requirements:
Group A beta hemolytic streptococci
Persistent of organism
Upper respiratory tract as the site of infection
Group A beta hemolytic streptococci
They are a complex group of organisms with respect to their extracellular products and their intracellular structure. The streptococcal cell wall consists of three layers: the outer layer formed by protein antigens, the middle layer containing group specific carbohydrates and an inner mucopeptide layer. The organism has a nonantigenic hyaluronate capsule, which does not play a significant role in its virulence. The protein layer contains three proteins - M, J and R proteins. The M protein antigen stimulates the production of type specific antibodies and is an immunologically distinct protein. It is the formation of these antibodies that constitutes the basis for the development of anti-streptococcal vaccines.
On the basis of polysaccharides in the middle layer of streptococcal walls, b hemolytic streptococci are divided into serologically distinct groups A, B, C, D etc. Certain members of Group A are definitely involved in the pathogenesis of acute rheumatic fever which are called rheumatogenic strains.
The inner layer of cell wall, which contains peptidoglycan, has been shown to produce subcutaneous nodules in rabbits, resembling these of acute rheumatic fever in human beings. The group A streptococci secrete 20 extracellular toxins and enzymes such as Streptolysin O and S, erythrogenic toxins etc. Streptolysin O is lethal when injected intravenously to experimental animals and causes myocardial damage and electrocardiographic changes. It is a potent antigen and causes antibody response in 80% of individuals following an untreated upper respiratory tract infection with Group A b hemolytic streptococci. The response occurs in a week, reaches its peak in 3 - 5 weeks and subsides in 4 - 6 months. For both initial and recurrent attacks, the risk of developing rheumatic fever after an untreated streptococcal upper respiratory tract infection increases with an increase in ASO response.
A susceptible host who develops rheumatic fever following an untreated upper respiratory tract streptococcal infection can be rendered susceptible by his genetic inheritance possibly influenced by his immune mechanism. Our knowledge regarding the genetic factors in rheumatic fever is rather incomplete. Although a consistent genetic pattern has not been discovered, there are some suggestions as to an occasional transmission of susceptibility by a recessive autosomal gene. Based on the present evidence it is believed that an inherited susceptibility with limited penetrance makes an individual susceptible to rheumatic fever.
In recent years, more attention has been paid to rheumatic fever as being an autoimmune disease. By the use of immunofluorescent techniques, Group A streptococci and human myocardial fibers have been shown to have common cross-reactive antigens. The cross reactive antigens are similar in some chemical features to the streptococcal M proteins.
The effect of socioeconomic factors on the prevalence of rheumatic fever has been known and it is well accepted that acute rheumatic fever is a disease of the indigent. Unfavorable socioeconomic conditions and crowding within homes leads to increased transmission of streptococcal infections, thus exposing the susceptible individuals to the organism. Lack of medical facilities or improper treatment of such infections are a factor which would contribute to the development of rheumatic fever.
Persistence of organism
The persistence of living streptococci has been considered to be an important factor in the pathogenesis of rheumatic fever. It has been shown that rheumatic fever can be prevented by administration of penicillin as late as nine days after streptococcal pharyngitis. It seems imperative that for rheumatic fever to develop the streptococci must persist for a certain period of time.
Site of Infection
An important, constant and neglected facet in the pathogenesis of rheumatic fever is the necessity that the initiating streptococcal infection should take place in upper respiratory tract. It has been shown that the cholesterol and lipid extract of skin inhibit both hemolytic activity and the autogenicity of streptolysin O. This could explain why impetigo does not lead to rheumatic fever.
The role of viruses in rheumatic fever is not at all clear. It is possible that viruses may be activated by streptococcus or vice versa.