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Acute rheumatic fever
New Developments
Acute Rheumatic
Fever
Ellen FL Wald, MD Rheumatic fever continues to be an important cause of acquired heart disease in children and young adults. From a worldwide perspective it is the leading cause of death as a result of cardiac disease in the first five decades of life. Although our basic understanding of the pathogenesis of acute rheumatic fever (ARF) has remained static, recent observations of a changing epidemiology have led to renewed interest in this clinical entity.
Diagnosis of ARF The-problem begins with a group A streptococcal pharyngeal infection in a susceptible host, usually a school-aged child. The pharyngeal infection may be associated with a typical and severe sore throat, atypical or mild respiratory symptoms, or no symptoms of illness at all. Group A streptococci (GAS) contain antigens that are immunologically cross-reactive with human cardiac tissue. Infection with the GAS stimulates the production of a panel of antibodies that crossreact with normal human connective tissue (autoantibodies) and that initiate an inflammatory response. After a latency period of 2 to 3 weeks, signs and symptoms of ARF develop in the untreated susceptible host (Table 1)-a variable number of major (arthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules) and minor manifestations (fever, arthralgias, prolonged P-R interval, leukocytosis, and elevation of the erythrocyte sedimentation rate and C-reactive protein). The diagnosis of ARF is suspected when the patient, on first examination, has two major criteria or one major and two minor criteria.’ With one exception (when the major criterion is chorea), there must be supporting evidence of a recent streptococcal infection, in the form of either a positive throat culture or serologic data (elevation of anti-streptolysin 0, anti-hyaluronidase, or anti-deoxyribonuclease B titers). The arthritis associated with ARF is a migratory polyarthritis that involves the medium-size joints, specifically, the elbows, wrists, ankles, and knees. Each joint is inflamed for several days and then the inflammation resolves. Pain, the most remarkable of the joint complaints, is frequently out of proportion to the degree of swelling or erythema. The total duration of skeletal involvement is almost always less than 1 month. Carditis is usually manifest as a significant murmur-most often mitral insufficiency followed by aortic insufficiency. Myocarditis and pericarditis (elements of pancarditis), if present, are accompaniments of the valvular problem. Carditis is the only major manifestation of ARF that results in residual disease. Often, acute attacks do not leave permanent scarring; however, severe or recurrent attacks may lead to debilitating disease and the need for eventual valve replacement, Ellen Ft. Wald, MD, is Chief, Division of Infectious of Pittburgh School of Medicine, Children’s Hospital Cm PROBL PEDIATR 1993;23:264-270. Copyright 0 1993 by Mosby-Year Book, Inc 00459380 93/$4.00 + .I0 53/l/48154
264
Current Problems in Pediatrics / August 1993
Diseases, Department of Pittsburgh, Pittsburgh,
of Pediatrics, Pennsylvania,
University
New Developments
TABLE 1 Jones Criteria (revised)’ Major Manifestations
Minor Manifestations
Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules
Clinical Previous rheumatic fever or rheumatic heart disease Arthralgia Fever Laboratory Leukocytosis Elevated erythrocyte sedimentation rate Elevated C-reactive protein Prolonged P-R interval
Supporting Evidence of Streptococcal Infection Positive throat culture Increased antibody titers Recent scarlet fever
The principal diagnostic modality has been auscultation. Current echocardiographic techniques permit visualization of mitral insufficiency that is not necessarily audible or hemodynamically significant. Whether echocardiographic results should be permitted as the sole evidence of carditis, in the absence of an audible murmur, is controversial. Chorea is a unique major manifestation of ARF, in that it may follow the preceding streptococcal pharyngitis by a prolonged latency period of 2 to 6 months. The problem is characterized by the gradual onset of purposeless movements of all extremities, leading to incoordination and difficulty in speaking. Emotional lability is nearly universal. Chorea most often affects prepubertal girls, and although very frustrating for and frightening to the patient, it is self-limited and completely reversible, usually lasting fewer than 6 months. Erythema marginatum and subcutaneous nodules are relatively uncommon major manifestations of ARF, occurring in no more than 10% of patients. The former is a flat or slightly raised, pink macule, with faded center and serpiginous edges found over the trunk and extremities. Subcutaneous nodules (previously associated with severe carditis) are firm, painless nodules that are present over the extensor surfaces of certain joints (particularly elbows, knees, and wrists) and in the occipital region or over the spinous processes of the thoracic and lumbar vertebrae. The minor criteria are best divided into clinical and laboratory parameters. The clinical criteria are fever, arthralgias, and a history of rheumatic fever or evidence of preexisting rheumatic heart disease. The latter is helpful only in attempts to make a diagnosis of recurrent rheumatic fever. Arthralgias cannot be used as a minor criterion if arthritis is a major one. The laboratory parameters consist of several acute-phase reactants, including leukocytosis and elevation of the erythrocyte sedimentation rate and C-reactive protein. All the acute-phase reactants count as only one minor criterion. Prolongation of the P-R interval on electrocardiogram can count as a minor criterion if carditis is not a major one. The strongest diagnoses of ARF are based on the presence of chorea or carditis. The weakest diagnosis is based on polyarthritis as a single major criterion with two minor criteria, such as fever and leukocytosis. Even when accompanied by serologic evidence of streptococcal infection, the constellation of arthritis, fever, and leukocytosis is consistent with several other clinical problems.
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New Developments
The Organism An examination of the ultrastructure of the streptococcal cell wall is essential to a fundamental understanding of the pathogenesis of rheumatic fever (Figure 1). The outermost layer of the streptococcus organism is the hyaluronic acid capsule. This capsular layer gives the organism its mucoid appearance when it grows on solid agar. The hyaluronic acid capsule has properties that enable the organism to resist phagocytosis and, accordingly, is a virulence factor.2 In addition, components of the hyaluronate are antigenic and initiate the development of antibodies that may be important in creating some of the pathologic changes that occur in rheumatic fever.3 Beneath the hyaluronic acid capsule is the protein layer of the cell wall, which contains the M proteins; these proteins are particularly important in a discussion of rheumatic fever. The GAS that cause infection in humans can be divided into at least 80 different serotypes according to their M proteins. Immunity to invasive infection with a particular serotype of GAS is a consequence of the development of antibody to the M protein. The immunity provided by the anti-M antibody protects against homologous infection but does not provide heterologous immunity to the other M serotypes. The M protein is also a virulence factor. Whereas not all M types are associated with ARF, GAS that are not M-typable do not cause ARF. The M protein, like the hyaluronic acid capsule, has antiphagocytic properties, The M protein blocks the production of C3 (ordinarily stimulated by bacterial polysaccharides) and thus impairs activation of the alternate complement pathway, which ordinarily permits opsonization of the GAS, thereby facilitating phagocytosis.4 The M protein is probably most important because of its antigenicity. Recent work has shown that there are two distinct groups of M proteins5 Group I M-protein molecules share an antigenic domain containing a repeating sequence of peptides on their surface that is found in most of the streptococcal serotypes that cause ARF. The finding of this antigenically conserved region in most serotypes that cause ARF raises a possibility for vaccine development. Unfortunately, this group shares certain epitopes with human heart tissue, including cardiac myosin and sarcolemmal membrane proteins. 67‘The group II M proteins do not have this repeat sequence, produce a substance known as serum opacity factor, and do not cause ARF.
Capsule Hyaluronic acid Cell Wall M-Protein l
l
Group Carbohydrate Mucopeptide Protoplast Membrane FIGURE
266
1 Cross section of the streptococcal cell wall
Current Problems in Pediatrics / August 1993
New Developments
Beneath the protein layer is the group-specific carbohydrate layer that enables characterization of the streptococcus as group A, B, C, and so on. It is this layer of the cell wall that is extracted in all the current diagnostic kits that provide rapid identification of GAS directly from throat swabs. The group A carbohydrate moiety N-acetylglucosamine cross-reacts with mammalian valvular glycoproteins, thereby providing another source of autoantibodies.’ The next layer of the cell wall is the mucopeptide. This layer contains peptidoglycan, the synthesis of which is impaired by the action of 8-lactam antimicrobials. The innermost layer of the streptococcal cell wail, the protoplast membrane, is a highly complex lipoprotein antigen.’ This streptococcal membrane structure shares a number of common antigenic determinants with mammalian tissues, including human glomerular basement membranes, human muscle sarcolemmal membranes, smooth muscle of blood vessel walls, and brain antigens (caudate nuclei).
Epidemiology The epidemiology of rheumatic fever has changed dramatically during the last 100 years. First described as a clinical syndrome in the late ninteenth century, ARF reached its peak intensity in the western world early in the first half of the twentieth century, after which it began to decline. ARF occurred primarily among impoverished populations that lived in crowded conditions, for whom medical care generally was unavailable. Students of the disease have attributed the early decrease in cases of ARF to general improvements in the standard of living, increases in socioeconomic status, and decreases in crowding. Although the decline in ARF accelerated after penicillin became widely available and was most precipitous between 1950 and 1980, it was a well-established pattern for several decades before antimicrobial agents were generally available. After decades of continuous decline in the incidence of ARF, the medical community was shocked by the abrupt occurrence, starting in 1984, of a major epidemic of rheumatic fever in Salt Lake City and the surrounding intermountain areas of Utah, Idaho, Nevada, and Wyoming.” During the first 18 months of the epidemic, 74 children were identified as having ARF, and by 1989 the number of cases had increased to 198. Substantial increases in the number of hospital admissions for ARF have also been reported from Columbus and Akron, Ohio”,‘2. Nashville and Memphis, Tennessee13; Dallas, Texas14; Pittsburgh, Pennsylvania”, 16; and New York City.” A further manifestation of the resurgence of ARF has been the occurrence of epidemics in two military training camps-an event that has not occurred in the United States for nearly three decades.‘*, ” Not surprisingly, there has been tremendous interest in this resurgence of ARF. Unlike the traditional experience with ARF, these new outbreaks have not been centered in the crowded, impoverished inner-city ghetto but have occurred primarily in children of white, middle-class families, many of whom live in suburban or rural neighborhoods.20 The return of ARF in the late 1980s albeit not in extreme proportions, compels a reconsideration of our understanding of previous epidemiologic trends. In actuality, the conventional explanation for the mid-twentieth century decline in the incidence of ARF (i.e., improved standard of living) was never entirely satisfactory. To lend credence to the notion that the decreasing incidence of ARF was a function of improvements in the standard of living, it must first be demonstrated that improvements in the standard of living have led to fewer cases of acute strep-
Current Problems in Pediatrics / August 1993
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New Developments
tococcal pharyngitis. In fact, there is no evidence to support this proposition.21-23 On the contrary, in the few geographic areas where accurate statistics have been maintained, the incidence of streptococcal pharyngitis has been unchanged since the beginning of the twentieth century. Furthermore, although it is certain that the widespread availability of antibiotics has resulted in dramatic reductions of ARF in some local areas,22 in general, the anticipated effect of antibiotics on the primary prevention of ARF is modest. Historically and currently, only about 30% of children who have rheumatic fever have a prodromal illness sufficiently symptomatic to prompt a visit to a physician. Because not all who visit the physician will be given a correct diagnosis and not all who are given a correct diagnosis are compliant, the actual impact of antimicrobials on the incidence of primary attacks of ARF will be less than theoretically anticipated. The best explanation for these changing patterns in the epidemiology of ARF rests on the concept of the “rheumatogenicity” of certain M serotypes of streptococci. The concept of rheumatogenicity implies that only certain M types (rather than all M types) have the capability of causing ARF. Supporting this idea is the recognition of so-called nephritogenic streptococci. It has been long appreciated that the number of “skin” and “throat” strains of GAS that are associated with poststreptococcal glomerulonephritis is limited. Furthermore, the occurrence of nephritis and rheumatic fever has almost never been documented in the same individual, which establishes, for all intents and purposes, that nephritogenic streptococci are not rheumatogenic. Another line of evidence supporting the concept of rheumatogenicity comes from experiences in the 1940s at Irvington House, a convalescent care facility in New York City for children who are recovering from rheumatic fever. Although the incidence of first episodes of ARF after untreated streptococcal pharyngitis was reported to be approximately 3%, the incidence of second or recurrent attacks of rheumatic fever after untreated streptococcal pharyngitis varied between 40% and EJO%.~~(This probably relates, at least in part, to identification of a subset of individuals who are genetically susceptible to the development of rheumatic fever.) With this in mind, consider that an epidemic of streptococcal pharyngitis caused by serotype M4 at the Irvington House in the pre-penicillin era resulted in no cases of recurrent rheumatic fever among the children in residence.25 Along these same lines, a 13-year follow-up study by Bisno and colleagues26 of 104 episodes of streptococcal infection (antibody proven) in patients known to have had a primary episode of ARF showed the recurrence rate to be extraordinarily low. These observations suggest the existence of many nonrheumatogenic strains of GAS. The existence of rheumatogenic and nonrheumatogenie GAS establishes a new framework on which to explain changes in the epidemiology of ARF. Long periods of low rates of rheumatic fever probably reflect times during which “rheumatogenic” streptococci have not been prevalent. In contrast, the current resurgence of ARF almost certainly is indicative of the reintroduction and circulation of “rheumatogenic” streptococci. Although fluctuation in the prevalence of bacterial species also requires explanation, such trends frequently have been observed for other agents (e.g., coagulase-positive staphylococci and group B streptococci in neonates with infections and Pseudomonas aeruginosa in neutropenic patients with leukemia). Another interesting observation regarding the epidemiology of ARF is its occurrence in Third World nations, where it currently accounts for 25% to 40% of all cardiovascular diseases.27 Although it was thought in the early 1930s that ARF did not occur in countries with tropical climates, it is now recognized to be a major and escalating problem in many industrialized areas of developing nations.28
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Current Problems in Pediatrics / August 1993
New Developments
Genetics and Vaccine Development Primary prevention of rheumatic fever is very desirable, especially in geographic areas where it accounts for a major proportion of cases of serious cardiovascular disease. However, antibiotic therapy is an incomplete solution because of the relative infrequency of symptomatic presentation of the acute streptococcal pharyngeal infection. Accordingly, the development of a vaccine to prevent ARF and identification of a high-risk group that is most susceptible to rheumatogenic streptococci are essential. Rheumatic fever tends to cluster in families, indicating that genetic factors must be important in the susceptibility to this nonsuppurative complication of streptococcal infection. However, investigation of twins for concordance of ARF showed it occurred in only 3 of 16 cases, a much lower rate than other diseases with a strong genetic predisposition2’ Standard investigation of histocompatibility antigen markers did not initially disclose any trends until race was taken into consideration In studies by Ayoub and colleagues3’ white patients who had ARF were found to have an increased frequency of human leukocyte antigen type DR4, whereas black patients who had ARF showed an increased frequency of type DR2. Another area of investigation that supports the clinical observation of family clusters of ARF is the search for B-cell markers. Certain B-cell alloantigens are expressed more often in patients with ARF than in patients with acute poststreptococcal glomerulonephritis or in a control population.31 This B-cell alloantigen is found in 20% of the general population; therefore the future use of monoclonal antibodies may enable identification of a group of individuals at high risk of contracting ARF. With the identification of a population at risk, use of a vaccine consisting of the antigenic components of rheumatogenic M serotypes would theoretically give rise to protective antibodies, thereby preventing ARF. The recent observation that there are a limited number of rheumatogenic streptococci provides some optimism that this task can be accomplished. Alternatively, recognition that an antigenitally conserved region of the M protein, shared by virtually all rheumatogenic streptococci, may be immunogenrc and may provide protective antibody is also very encouraging, 32, 33 The potential problem that remains is the necessity of separating protective epitopes on the M protein from cross-reacting antigens that cause clinical manifestations of ARF. Although this may prove to be a Herculean task, it is hoped that current expertise in molecular biologic and immunologic techniques will enable its successful accomplishment.
Acknowledgments
The author gratefully acknowledges Barry Dashefsky, MD. for his review of the manuscript and An&a DrMatteo for secretarial assistance.
References 1 Ad Hoc Committee to Revise the Jones Criterra (Modified) of the Councrl on and Congenital Heart Disease of the American Heart Assocration. Jones criteria ante In the dragnosrs of rheumatrc fever) Circulat!on 1984; 69,204A-208A. 2 Foley MJ. Wood WB Jr. Studies on the pathogenrcity of group A streptococci, effects of the M proteins and the capsular gel J Exp Med 1959; 1 lo:61 7-628 3. Frllrt HM, Blake M. MacDonald C. McCarty M, lmmunogenrcrty of Irposome-bound mice J Exp Med 1988, 168:971-982. 4. Brsno AL. Alternate complement pathway activation by group A streptococcr. infect lmmun 1979, 26.11721176.
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Rheumatic Fever (revised for gurdII antrphagocytrc hyaluronate
in
role of M protern.
in Pediatrics
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1993
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5. Bessen D, Jones KF, Fischetti VA: Evidence for two distinct classes of streptococcal M protein and their relationship to rheumatic fever. d Exp Med 1989; 169:269-283. 6. Dale JB, Beachey EH: Sequence of myosin-cross-reactive epitopes of streptococcal M protein. J Exp Med 1986; 164: 1785- 1790. 7. Dale JB, Beachey EH: Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart. J Exp Med 1982; 156:1165-l 176. 8. Goldstein I, Rebeyrotte P, Parlebas J, Halpern B: Isolation from heart valves of glycopeptides, which show immunological properties wrth Streptococcus haemolyticus group A polysaccharides. Nature 1968; 219.866-868. 9. Zabnskie JB: Rheumatic fever the Interplay between host, genetics and microbe. Circular/on 1985, 71:107771086. 10. Veasey LG, Wiedmeier SE, Orsmond GS, et al: Resurgence of acute rheumatic fever in the Intermountain area of the United States. N Engl J Med 1987; 316:421-427. 11 Hosier DM, Craenen JM, Teske DW, Wheller JJ: Resurgence of acute rheumatic fever Am J DLS Child 1987, 141:730-733. 12. Congeni B, Riggo C, Congeni J, Sreenavason VV: Outbreak of acute rheumatic fever in northeast Ohio. J fed&r 1987; 111:176-179 13. Westlake RM. Graham TP, Edwards KM: An outbreak of acute rheumatic fever in Tennessee. Pediatr infect Dis J 1990; 9:97- 100. 14. Burns DL, Ginsburg CM: Recrudescence of acute rheumatic fever in Dallas, Texas [Abstract 4961: proceedings of the Society for Pediatric Research. Pediatr Res 1987; 21.256A. 15. Wald ER, Dashefsky 6, Feidt C, Chiponis D, Byers C: Acute rheumatic fever in western Pennsylvania and the tri-state area. Ped/africs 1987; 80:371-374. 16. Zangwill KM, Wald ER, Londino AV: Acute rheumatic fever in western Pennsylvanra: a persistent problem into the 1990s. d Pediatr 1991; 118:561-563. 17. Griffiths PS, Gersony WM: Acute rheumatic fever in New York City (19691988): a comparative study of two decades. J Pediatr 1990; 116:882-887. 18. Wallace MR, Garst PD, Papadimos TJ, Oldfield EC Ill: The return of acute rheumatic fever in young adults. JAMA 1989; 262:2557-2561. 19. Centers for Disease Control: Acute rheumatic fever among army trainees: Fort Leonard Wood, Missouri, 198771988. MMWR 1988; 375199522. 20. Bisno AL: Group A streptococcal infections and acute rheumatic fever. N Engl J Med 1991; 3251783-793. 21. Dajani A: Current status of non-suppurative complications of group A streptococci. Pediatr Infect Dis J (Supplement) 1991; 10:525-527. 22. Gordis L: Effectiveness of comprehensive-care programs In preventing rheumatic fever. N Engl J bled 1973; 289:331--335. 23. Gordis L: The virtual disappearance of rheumatic fever in the Unrted States, lessons in the rise and fall of disease. Circulation 1985; 72: 1155 1162. 24. Taranta A, Wood HF, Feinstein AR, et al: Rheumatrc fever in children and adolescents, IV, relation of the rheumatic fever recurrence rate per streptococcal infection to the titers of streptococcal antibodies. Ann intern Med 1964; 6O(suppl 5):47-57 25. Kuttner AG, Krumwiede E: Observations on the effect of streptococcal upper respiratory rnfections on rheumatic children: a three-year study. J C/in invest 1941( 20273-287. 26. Bisno AL, Pearce IA, Stollerman GH: Streptococcal infections that fail to cause recurrences of rheumatic fever. J Infect Dis 1977; 136.2788285. 27. Agarwal BL: Rheumatic heart disease unabated In developing countries. Lancet 1981; 2.90 28. Stollerman GH: Rheumatogenic group A streptococci and the return of rheumatrc fever Adv Intern Med 1990; 35,1-26. 29. Taranta A, Torosday S, Metrakos JD, et al: Rheumatic fever in monozygotrc and drrygotic twins C/rcu/ation 1959, 20:778. 30 Ayoub EM, Barrett DJ. MacLaren NK, Krischer JP- Association of class II human hrstocompattbility leucocyte antigens wrth rheumatic fever J C//n invest 1986; 77.201 g-2026. 31. Zabnskie JB, Lavenchy D, Williams RC Jr, et al. Rheumatic fever-associated B cell alloantigens as identified by monoclonal antibodies. Arthrh Rheum 1985; 28:10471051, 32 Bessen D, Frschetti VA: Influence of intranasal immunization with synthetic peptrdes corresponding to conserved epitopes of M protein on mucosal colonization by group A streptococcr. infect lmmun 1988: 56.2666-2672 33 Fischetti VA, Hodges WM, Hruby DE: Protection agatnst streptococcal pharyngeal colonization with vaccinia: M protein recombinant. Science 1989; 244:14871490,
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Current Problems in Pediatrics i August 1993
Acute Rheumatic
Fever
Ellen FL Wald, MD Rheumatic fever continues to be an important cause of acquired heart disease in children and young adults. From a worldwide perspective it is the leading cause of death as a result of cardiac disease in the first five decades of life. Although our basic understanding of the pathogenesis of acute rheumatic fever (ARF) has remained static, recent observations of a changing epidemiology have led to renewed interest in this clinical entity.
Diagnosis of ARF The-problem begins with a group A streptococcal pharyngeal infection in a susceptible host, usually a school-aged child. The pharyngeal infection may be associated with a typical and severe sore throat, atypical or mild respiratory symptoms, or no symptoms of illness at all. Group A streptococci (GAS) contain antigens that are immunologically cross-reactive with human cardiac tissue. Infection with the GAS stimulates the production of a panel of antibodies that crossreact with normal human connective tissue (autoantibodies) and that initiate an inflammatory response. After a latency period of 2 to 3 weeks, signs and symptoms of ARF develop in the untreated susceptible host (Table 1)-a variable number of major (arthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules) and minor manifestations (fever, arthralgias, prolonged P-R interval, leukocytosis, and elevation of the erythrocyte sedimentation rate and C-reactive protein). The diagnosis of ARF is suspected when the patient, on first examination, has two major criteria or one major and two minor criteria.’ With one exception (when the major criterion is chorea), there must be supporting evidence of a recent streptococcal infection, in the form of either a positive throat culture or serologic data (elevation of anti-streptolysin 0, anti-hyaluronidase, or anti-deoxyribonuclease B titers). The arthritis associated with ARF is a migratory polyarthritis that involves the medium-size joints, specifically, the elbows, wrists, ankles, and knees. Each joint is inflamed for several days and then the inflammation resolves. Pain, the most remarkable of the joint complaints, is frequently out of proportion to the degree of swelling or erythema. The total duration of skeletal involvement is almost always less than 1 month. Carditis is usually manifest as a significant murmur-most often mitral insufficiency followed by aortic insufficiency. Myocarditis and pericarditis (elements of pancarditis), if present, are accompaniments of the valvular problem. Carditis is the only major manifestation of ARF that results in residual disease. Often, acute attacks do not leave permanent scarring; however, severe or recurrent attacks may lead to debilitating disease and the need for eventual valve replacement, Ellen Ft. Wald, MD, is Chief, Division of Infectious of Pittburgh School of Medicine, Children’s Hospital Cm PROBL PEDIATR 1993;23:264-270. Copyright 0 1993 by Mosby-Year Book, Inc 00459380 93/$4.00 + .I0 53/l/48154
264
Current Problems in Pediatrics / August 1993
Diseases, Department of Pittsburgh, Pittsburgh,
of Pediatrics, Pennsylvania,
University
New Developments
TABLE 1 Jones Criteria (revised)’ Major Manifestations
Minor Manifestations
Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules
Clinical Previous rheumatic fever or rheumatic heart disease Arthralgia Fever Laboratory Leukocytosis Elevated erythrocyte sedimentation rate Elevated C-reactive protein Prolonged P-R interval
Supporting Evidence of Streptococcal Infection Positive throat culture Increased antibody titers Recent scarlet fever
The principal diagnostic modality has been auscultation. Current echocardiographic techniques permit visualization of mitral insufficiency that is not necessarily audible or hemodynamically significant. Whether echocardiographic results should be permitted as the sole evidence of carditis, in the absence of an audible murmur, is controversial. Chorea is a unique major manifestation of ARF, in that it may follow the preceding streptococcal pharyngitis by a prolonged latency period of 2 to 6 months. The problem is characterized by the gradual onset of purposeless movements of all extremities, leading to incoordination and difficulty in speaking. Emotional lability is nearly universal. Chorea most often affects prepubertal girls, and although very frustrating for and frightening to the patient, it is self-limited and completely reversible, usually lasting fewer than 6 months. Erythema marginatum and subcutaneous nodules are relatively uncommon major manifestations of ARF, occurring in no more than 10% of patients. The former is a flat or slightly raised, pink macule, with faded center and serpiginous edges found over the trunk and extremities. Subcutaneous nodules (previously associated with severe carditis) are firm, painless nodules that are present over the extensor surfaces of certain joints (particularly elbows, knees, and wrists) and in the occipital region or over the spinous processes of the thoracic and lumbar vertebrae. The minor criteria are best divided into clinical and laboratory parameters. The clinical criteria are fever, arthralgias, and a history of rheumatic fever or evidence of preexisting rheumatic heart disease. The latter is helpful only in attempts to make a diagnosis of recurrent rheumatic fever. Arthralgias cannot be used as a minor criterion if arthritis is a major one. The laboratory parameters consist of several acute-phase reactants, including leukocytosis and elevation of the erythrocyte sedimentation rate and C-reactive protein. All the acute-phase reactants count as only one minor criterion. Prolongation of the P-R interval on electrocardiogram can count as a minor criterion if carditis is not a major one. The strongest diagnoses of ARF are based on the presence of chorea or carditis. The weakest diagnosis is based on polyarthritis as a single major criterion with two minor criteria, such as fever and leukocytosis. Even when accompanied by serologic evidence of streptococcal infection, the constellation of arthritis, fever, and leukocytosis is consistent with several other clinical problems.
Current Problems in Pediatrics i August 1993
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New Developments
The Organism An examination of the ultrastructure of the streptococcal cell wall is essential to a fundamental understanding of the pathogenesis of rheumatic fever (Figure 1). The outermost layer of the streptococcus organism is the hyaluronic acid capsule. This capsular layer gives the organism its mucoid appearance when it grows on solid agar. The hyaluronic acid capsule has properties that enable the organism to resist phagocytosis and, accordingly, is a virulence factor.2 In addition, components of the hyaluronate are antigenic and initiate the development of antibodies that may be important in creating some of the pathologic changes that occur in rheumatic fever.3 Beneath the hyaluronic acid capsule is the protein layer of the cell wall, which contains the M proteins; these proteins are particularly important in a discussion of rheumatic fever. The GAS that cause infection in humans can be divided into at least 80 different serotypes according to their M proteins. Immunity to invasive infection with a particular serotype of GAS is a consequence of the development of antibody to the M protein. The immunity provided by the anti-M antibody protects against homologous infection but does not provide heterologous immunity to the other M serotypes. The M protein is also a virulence factor. Whereas not all M types are associated with ARF, GAS that are not M-typable do not cause ARF. The M protein, like the hyaluronic acid capsule, has antiphagocytic properties, The M protein blocks the production of C3 (ordinarily stimulated by bacterial polysaccharides) and thus impairs activation of the alternate complement pathway, which ordinarily permits opsonization of the GAS, thereby facilitating phagocytosis.4 The M protein is probably most important because of its antigenicity. Recent work has shown that there are two distinct groups of M proteins5 Group I M-protein molecules share an antigenic domain containing a repeating sequence of peptides on their surface that is found in most of the streptococcal serotypes that cause ARF. The finding of this antigenically conserved region in most serotypes that cause ARF raises a possibility for vaccine development. Unfortunately, this group shares certain epitopes with human heart tissue, including cardiac myosin and sarcolemmal membrane proteins. 67‘The group II M proteins do not have this repeat sequence, produce a substance known as serum opacity factor, and do not cause ARF.
Capsule Hyaluronic acid Cell Wall M-Protein l
l
Group Carbohydrate Mucopeptide Protoplast Membrane FIGURE
266
1 Cross section of the streptococcal cell wall
Current Problems in Pediatrics / August 1993
New Developments
Beneath the protein layer is the group-specific carbohydrate layer that enables characterization of the streptococcus as group A, B, C, and so on. It is this layer of the cell wall that is extracted in all the current diagnostic kits that provide rapid identification of GAS directly from throat swabs. The group A carbohydrate moiety N-acetylglucosamine cross-reacts with mammalian valvular glycoproteins, thereby providing another source of autoantibodies.’ The next layer of the cell wall is the mucopeptide. This layer contains peptidoglycan, the synthesis of which is impaired by the action of 8-lactam antimicrobials. The innermost layer of the streptococcal cell wail, the protoplast membrane, is a highly complex lipoprotein antigen.’ This streptococcal membrane structure shares a number of common antigenic determinants with mammalian tissues, including human glomerular basement membranes, human muscle sarcolemmal membranes, smooth muscle of blood vessel walls, and brain antigens (caudate nuclei).
Epidemiology The epidemiology of rheumatic fever has changed dramatically during the last 100 years. First described as a clinical syndrome in the late ninteenth century, ARF reached its peak intensity in the western world early in the first half of the twentieth century, after which it began to decline. ARF occurred primarily among impoverished populations that lived in crowded conditions, for whom medical care generally was unavailable. Students of the disease have attributed the early decrease in cases of ARF to general improvements in the standard of living, increases in socioeconomic status, and decreases in crowding. Although the decline in ARF accelerated after penicillin became widely available and was most precipitous between 1950 and 1980, it was a well-established pattern for several decades before antimicrobial agents were generally available. After decades of continuous decline in the incidence of ARF, the medical community was shocked by the abrupt occurrence, starting in 1984, of a major epidemic of rheumatic fever in Salt Lake City and the surrounding intermountain areas of Utah, Idaho, Nevada, and Wyoming.” During the first 18 months of the epidemic, 74 children were identified as having ARF, and by 1989 the number of cases had increased to 198. Substantial increases in the number of hospital admissions for ARF have also been reported from Columbus and Akron, Ohio”,‘2. Nashville and Memphis, Tennessee13; Dallas, Texas14; Pittsburgh, Pennsylvania”, 16; and New York City.” A further manifestation of the resurgence of ARF has been the occurrence of epidemics in two military training camps-an event that has not occurred in the United States for nearly three decades.‘*, ” Not surprisingly, there has been tremendous interest in this resurgence of ARF. Unlike the traditional experience with ARF, these new outbreaks have not been centered in the crowded, impoverished inner-city ghetto but have occurred primarily in children of white, middle-class families, many of whom live in suburban or rural neighborhoods.20 The return of ARF in the late 1980s albeit not in extreme proportions, compels a reconsideration of our understanding of previous epidemiologic trends. In actuality, the conventional explanation for the mid-twentieth century decline in the incidence of ARF (i.e., improved standard of living) was never entirely satisfactory. To lend credence to the notion that the decreasing incidence of ARF was a function of improvements in the standard of living, it must first be demonstrated that improvements in the standard of living have led to fewer cases of acute strep-
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tococcal pharyngitis. In fact, there is no evidence to support this proposition.21-23 On the contrary, in the few geographic areas where accurate statistics have been maintained, the incidence of streptococcal pharyngitis has been unchanged since the beginning of the twentieth century. Furthermore, although it is certain that the widespread availability of antibiotics has resulted in dramatic reductions of ARF in some local areas,22 in general, the anticipated effect of antibiotics on the primary prevention of ARF is modest. Historically and currently, only about 30% of children who have rheumatic fever have a prodromal illness sufficiently symptomatic to prompt a visit to a physician. Because not all who visit the physician will be given a correct diagnosis and not all who are given a correct diagnosis are compliant, the actual impact of antimicrobials on the incidence of primary attacks of ARF will be less than theoretically anticipated. The best explanation for these changing patterns in the epidemiology of ARF rests on the concept of the “rheumatogenicity” of certain M serotypes of streptococci. The concept of rheumatogenicity implies that only certain M types (rather than all M types) have the capability of causing ARF. Supporting this idea is the recognition of so-called nephritogenic streptococci. It has been long appreciated that the number of “skin” and “throat” strains of GAS that are associated with poststreptococcal glomerulonephritis is limited. Furthermore, the occurrence of nephritis and rheumatic fever has almost never been documented in the same individual, which establishes, for all intents and purposes, that nephritogenic streptococci are not rheumatogenic. Another line of evidence supporting the concept of rheumatogenicity comes from experiences in the 1940s at Irvington House, a convalescent care facility in New York City for children who are recovering from rheumatic fever. Although the incidence of first episodes of ARF after untreated streptococcal pharyngitis was reported to be approximately 3%, the incidence of second or recurrent attacks of rheumatic fever after untreated streptococcal pharyngitis varied between 40% and EJO%.~~(This probably relates, at least in part, to identification of a subset of individuals who are genetically susceptible to the development of rheumatic fever.) With this in mind, consider that an epidemic of streptococcal pharyngitis caused by serotype M4 at the Irvington House in the pre-penicillin era resulted in no cases of recurrent rheumatic fever among the children in residence.25 Along these same lines, a 13-year follow-up study by Bisno and colleagues26 of 104 episodes of streptococcal infection (antibody proven) in patients known to have had a primary episode of ARF showed the recurrence rate to be extraordinarily low. These observations suggest the existence of many nonrheumatogenic strains of GAS. The existence of rheumatogenic and nonrheumatogenie GAS establishes a new framework on which to explain changes in the epidemiology of ARF. Long periods of low rates of rheumatic fever probably reflect times during which “rheumatogenic” streptococci have not been prevalent. In contrast, the current resurgence of ARF almost certainly is indicative of the reintroduction and circulation of “rheumatogenic” streptococci. Although fluctuation in the prevalence of bacterial species also requires explanation, such trends frequently have been observed for other agents (e.g., coagulase-positive staphylococci and group B streptococci in neonates with infections and Pseudomonas aeruginosa in neutropenic patients with leukemia). Another interesting observation regarding the epidemiology of ARF is its occurrence in Third World nations, where it currently accounts for 25% to 40% of all cardiovascular diseases.27 Although it was thought in the early 1930s that ARF did not occur in countries with tropical climates, it is now recognized to be a major and escalating problem in many industrialized areas of developing nations.28
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Genetics and Vaccine Development Primary prevention of rheumatic fever is very desirable, especially in geographic areas where it accounts for a major proportion of cases of serious cardiovascular disease. However, antibiotic therapy is an incomplete solution because of the relative infrequency of symptomatic presentation of the acute streptococcal pharyngeal infection. Accordingly, the development of a vaccine to prevent ARF and identification of a high-risk group that is most susceptible to rheumatogenic streptococci are essential. Rheumatic fever tends to cluster in families, indicating that genetic factors must be important in the susceptibility to this nonsuppurative complication of streptococcal infection. However, investigation of twins for concordance of ARF showed it occurred in only 3 of 16 cases, a much lower rate than other diseases with a strong genetic predisposition2’ Standard investigation of histocompatibility antigen markers did not initially disclose any trends until race was taken into consideration In studies by Ayoub and colleagues3’ white patients who had ARF were found to have an increased frequency of human leukocyte antigen type DR4, whereas black patients who had ARF showed an increased frequency of type DR2. Another area of investigation that supports the clinical observation of family clusters of ARF is the search for B-cell markers. Certain B-cell alloantigens are expressed more often in patients with ARF than in patients with acute poststreptococcal glomerulonephritis or in a control population.31 This B-cell alloantigen is found in 20% of the general population; therefore the future use of monoclonal antibodies may enable identification of a group of individuals at high risk of contracting ARF. With the identification of a population at risk, use of a vaccine consisting of the antigenic components of rheumatogenic M serotypes would theoretically give rise to protective antibodies, thereby preventing ARF. The recent observation that there are a limited number of rheumatogenic streptococci provides some optimism that this task can be accomplished. Alternatively, recognition that an antigenitally conserved region of the M protein, shared by virtually all rheumatogenic streptococci, may be immunogenrc and may provide protective antibody is also very encouraging, 32, 33 The potential problem that remains is the necessity of separating protective epitopes on the M protein from cross-reacting antigens that cause clinical manifestations of ARF. Although this may prove to be a Herculean task, it is hoped that current expertise in molecular biologic and immunologic techniques will enable its successful accomplishment.
Acknowledgments
The author gratefully acknowledges Barry Dashefsky, MD. for his review of the manuscript and An&a DrMatteo for secretarial assistance.
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