Worldwide Control of Rheumatic Fever T H E W O R L D H E A L T H O R G A N I Z A T I O N convened a meet-

ing of expert staff members and consultants in Geneva during 1977 to consider the prospects for worldwide rheumatic fever control. Their report, published subsequently as a W H O memorandum (1), points out the fact that although acute rheumatic fever is relatively rare nowadays in developed countries of the western world, "in developing countries of the tropics and subtropics rheumatic heart disease is the commonest form of heart disease, often of very great severity as it used to be observed in Europe a century ago." Indeed, "rheumatic heart disease prevalence rates as high as 22 per thousand and even 33 per thousand have been reported in schoolaged children in urban slums of some developing countries." T h e W H O memorandum further emphasizes that "chronic crippling rheumatic heart disease may be prevented, to a great extent, by adequate prophylactic measures. T h e persistence of a largely preventable disease should bring it automatically into the focus of medical attention." Why, indeed, should acute rheumatic fever and rheumatic heart disease persist, taking such a tragic toll in morbidity and mortality among young people, when control requires only the proper treatment and prevention of upper respiratory infections due to the group A streptococcus, an organism that has remained exquisitely sensitive to penicillin? T h e answer lies in inherent defects in our two major strategies for control: "primary prevention" and "secondary prevention." "Primary prevention" entails adequate diagnosis and treatment of streptococcal sore throat. Unfortunately, in many of the developing countries, high population densities within indigent "ghetto" communities and individual family dwelling units provide ideal epidemiologic circumstances for the person-to-person spread of virulent streptococcal strains. Children with self-limited illnesses such as sore throats may never come to medical attention, and throat culture services are usually unavailable to aid in diagnosis. Moreover, in one third or more of cases, acute rheumatic fever may arise after a very mild or even clinically inapparent upper respiratory infection. "Secondary prevention" depends upon continuous antimicrobial prophylaxis of streptococcal infection among patients who have experienced an attack of acute rheumatic fever, because such persons are at inordinate risk of recurrences after intercurrent episodes of "strep throat." It obviously takes a high degree of public health organization to identify rheumatic subjects, get them into prophylactic programs, and assure fidelity of prophylaxis. Moreover, there are no firm guidelines as to how long 918

individuals should stay on continuous prophylaxis and when they may switch from monthly benzathine penicillin G injections to oral sulfonamides, penicillin, or erythromycin. Indeed, the efficacy of these latter regimens, particularly in adults, has been called into question (2). New approaches to worldwide rheumatic fever control are thus urgently needed. Several such approaches bear consideration, at least on a theoretical basis. T h e first is to identify those persons in the general population uniquely susceptible to rheumatic fever (if such exist) so that they may be placed under intensive prospective surveillance for streptococcal infection. Unfortunately, genetic analyses of rheumatic subjects have thus far failed to provide solid, consistent evidence of a specific H L A type that might identify a rheumatic diathesis. Recently, however, Patarroyo and colleagues (3) have identified a B-cell alloantigen present in over 7 0 % of rheumatic patients tested in New York City and Bogota, Columbia, as opposed to only 17% of race- and sex-matched control subjects. These findings must obviously be confirmed in diverse geographic settings, but they give hope that we might in the future be able to focus our control efforts much more sharply. A second approach involves the prevention of streptococcal colonization. A particular cell wall constituent, lipoteichoic acid, appears to be the specific ligand responsible for binding of group A streptococci to oral epithelial cells. In vitro, coating of epithelial cells with lipoteichoic acid or of streptococci with antibodies to lipoteichoic acid prevents binding of the organisms to oral epithelium (4). Although still hypothetical, the possibility of doing similar manipulations in vivo and thus interfering with the earliest stages of host-parasite interaction is most intriguing. Just as one would like to identify the particularly susceptible host, it would be most helpful to identify streptococcal strains most likely to initiate acute rheumatic fever. A growing body of epidemiologic and bacteriologic evidence supports the concept that group A streptococci may vary in their rheumatogenic potential. Such a hypotheses is consistent with observed geographic and temporal variations in the incidence of acute rheumatic fever. Studies of outbreaks of streptococcal pharyngitis reveal that certain serotypes, such as type 5, are particularly prone to give rise to acute rheumatic fever, while others (for example, types 4 and 12) do so rarely, if ever (5). Investigations of endemic cases in Trinidad (6) and Memphis, Tennessee, indicate that strains causing this sequel belong to different serotypes than those causing acute glomerulonephritis in the same populations. The trick is

December 1979 • Annals of Internal Medicine • Volume 91 • Number 6

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to identify biologic markers of rheumatogenicity. Several have been suggested and are being evaluated. In addition to alerting us to truly dangerous streptococcal infections, ready identification of rheumatogenic streptococci would be a sine qua non in formulating future group A streptococcal vaccines, because there are over 60 known serotypes. This latter area of vaccine development holds the most promise in the long run for solving the worldwide problem of rheumatic heart disease. We have known for many years that M protein, located on the outermost surface of group A streptococci, is the organisms principal virulence factor and that antibodies to M protein provide type-specific acquired immunity to infection. Why, then, has a multivalent M protein vaccine (analogous, say, to pneumococcal polysaccharide vaccine) not been manufactured and marketed? The reason is that most so-called "purified" M protein preparations contain, in addition to the type-specific determinant, a number of non-type-specific antigens that are common to many serotypes, that give rise to local and systemic toxic reactions, and that could not be exonerated with complete confidence as possible culprits in the pathogenesis of acute rheumatic fever. Several groups have been working on the problems of M protein purification (7) with varying degrees of success, and some encouraging clinical trials have been reported (8). The exciting new development has been a breakthrough in M protein purification techniques by which the type-specific protective determinant has finally been freed from these non-type-specific antigens (9). The result has been a product that is immunogenic and surprisingly nontoxic. The new vaccine (thus far only one serotype has been tested in humans) elicits protective antibodies in human volunteers, but such volunteers do not develop heart-reactive antibodies or other potentially deleterious humoral responses even after multiple booster doses (10). While the World Health Organization quite appropriately rededicates itself to primary and secondary prevention of rheumatic fever, it is comforting to know that more

innovative approaches may be in the offing. Nirvana for the streptococcologist will be the day when immunogenic, nontoxic vaccines, specifically formulated to contain locally prevalent rheumatogenic strains, are administered to those persons who are, on constitutional or epidemiologic grounds, at greatest risk of acute rheumatic fever. Even though aspirations to such an ideal state may well prove naive, there is, for the first time in many years, a reasonable basis for optimism. ( A L A N L. BISNO, M.D.; Division of Infectious Diseases, Department of Medicine, University of Tennessee Center for the Health Sciences; Memphis, Tennessee) References 1. E L K H O L Y A, R O T T A J, W A N N A M A K E R LW, et al. Recent advances in

rheumatic fever control and future prospects: A W H O memorandum. Bull WHO. 1978;56:887-912. 2. BISNO AL, P E A R C E IA, S T O L L E R M A N G H . Streptococcal

3. P A T A R R O Y O ME, W I N C H E S T E R RJ, V E J E R A N O A, et al. Association of

a B-cell alloantigen with susceptibility to rheumatic fever. Nature. 1979;278:173-4. 4. BEACHEY EH, O F E K I. Epithelial cell binding of group A streptococci by lipoteichoic acid on fimbriae denuded of M protein. / Exp Med. 1976;143:759-71. 5. BISNO AL. The concept of rheumatogenic and nonrheumatogenic group A streptococci. In: M C C A R T Y M, ZABRISKIE JB, eds. Streptococcal Infections and The Immune Response. New York: Academic Press; In press. 6. P O T T E R EV, S V A R T M A N M, M O H A M M E D I, C o x R, P O O N - K I N G T,

EARLE DP. Tropical acute rheumatic fever and associated streptococcal infections compared with concurrent acute glomerulonephritis. / Pediatr. 1978;92:325-33. 7. F I S C H E T T I VA, G O T S C H L I C H EC, SIVIGLIA G, Z A B R I S K I E JB. Strepto-

coccal M protein extracted by nonionic detergent: I. Properties of the antiphagocytic and type-specific molecules. J Exp Med. 1976;144:32-53. 8. D ' A L E S S A N D R I R, P L O T K I N G, K L U G E RM, et al. Protective studies

with group A streptococcal M protein vaccine: III. Challenge of volunteers after systemic or intranasal immunization with type 3 or type 12 group A Streptococcus. J Infect Dis. 1978;138:712-8. 9. B E A C H E Y EH, C H I A N G EY, SEYER J M , K A N G A H , C H I A N G T M ,

STOLLERMAN G H . Separation of the type specific M protein from toxic cross reactive antigens of group A streptococci. Trans Assoc Am Physicians. 1977;90:390-400. 10. B E A C H E Y EH, S T O L L E R M A N G H , J O H N S O N R H , O F E K I, BISNO AL

Human immune response to immunization with a structurally defined polypeptide fragment of streptococcal M protein. / Exp Med. 1979;150:862-77. ©1979 American College of Physicians

Editorial Note

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which fail to cause recurrences of rheumatic fever. / Infect Dis. 1977;136:278-85.


Worldwide control of rheumatic fever.

Worldwide Control of Rheumatic Fever T H E W O R L D H E A L T H O R G A N I Z A T I O N convened a meet- ing of expert staff members and consultants...
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