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THE RESURGENCE OF ACUTE Annu. Rev. Med. 1990.41:319-329. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/28/15. For personal use only.
RHEUMATIC FEVER IN THE UNITED STATESl Alan L. Bisno, M.D. Medical Service, Miami Veterans Administration Medical Center, Miami, Florida 33125; and Departm ent of Medi cin e ,
University of Miami School of Medicine, Miami, Florida KEY WORDS:
streptococcus group A, heart disease, epidemiology, disease prevention, streptococcal pharyngitis.
ABSTRACT
The incidence of acute rheumatic fever (ARF) had been decl i ning in t he United States for decades, and by the late 1970s ARF had become a rare disease in most areas of the country. The mid-1980s saw a resurgence of ARF, with reported outbreaks in Utah, Ohio, Pennsylvania, and military recruit camps in Missouri and California, as well as sporadic cases in many other communities. This review summarizes salient epidemiologic data related to the resurgence, explores some possible explanations for its occur
rence, and discusses strategies for prevention of rheumatic fever now and in the future. INTRODUCTION Since the end of World War II, there has been a dramatic decline in the in ciden ce of acute rheumatic fever (ARF) in the United States. This decline
is readily apparent in the closure or reassignment of the famous rheu matic fever sanitaria (e.g. Irvington House outside New York City, La Rabida in Chicago, House of the Good Samaritan in Boston) and in the I
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unfamiliarity of younger physicians with the clinical manifestations of the disease. The magnitude of t he decline can be documented more precisely in selected geographic locales where reliable sequential data are available. For example, the incidence of ARF among school-aged children in Rochester, Minnesota, decreased from 65 per 100,000 in 1935-1949 to 41 in 1950-1964 to 9 in 1965-1978
(1).
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In the quarter century between 1960 and 1985, the rate of decline was particularly steep. The annual incidence (hospitalized cases only) of ARF among persons aged 5 to 19 years in Baltimore, Maryland, plummeted from 15.6 per 100,000 in 1960-1964 to approximately 0.5 in 1977-1981
(2, 3). Similar extremely low incidence figures have been reported in recent years by investigators from Rhode Island to California (4). In a careful, community-wide survey conducted by the author and colleagues in Memphis-Shelby County, Tennessee, the incidence of ARF among school-aged children during 1977-1981 was 1.88 per 100,000 overall and only 0.5 in the more affluent suburbs. The latter finding prompted us to describe ARF in the early 1980s as "a vanishing disease in suburbia"
(5).
The virtual disappearance of ARF as a significant public health problem is not unique to the United States. Similar trends are apparent in the major wcstern industrialized countries and in Asia as well (6, 7). In contrast, ARF continues to be among the most important causes of cardiovascular morbidity and mortality in the Indian subcontinent, the Arab countries of the Middle East, and many other developing nations of the world. In Sri Lanka in 1978, for example, the morbidity rate of ARF was 47 per 100,000 for the population as a whole and over 140 for those aged 5 to 19 years (8). At the medical college in Allahabad, India, rheumatic heart disease accounts for approximately 40% of cardiac admissions, a proportion that remained essentially constant between 1966 and 1980 (9).
What Caused the Decline in Rheumatic Fever? There has been intense speculation as to the reasons for the dramatic decline in ARF incidence in the US and other highly industrialized coun tries. Several factors have been pinpointed, but none appears sufficient by itself to explain the phenomenon. The first factor is an improvement in the general standard of living. Certainly, ARF tends to thrive on poverty. This is true not only on a global basis but even in individual communities. In the US, for example, ARF incidence is much lower among affluent, usually Caucasian, populations than in the impoverished black or Hispanic ghettos of our urban metropolises
(2, 5, 10). The link between socio
economic status and ARF incidence is unexplained. It could be related to factors such as nutrition, hygiene, and access to medical care. One critical
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variable, however, may be household and bedroom crowding, conditions known to predispose to the interpersonal transmission of group A strep tococci (11). Clearly, penicillin played a significant role in the post-World War II decline in ARF morbidity and mortality, particularly in preventing recur rences of the disease. It is unlikely however, that antibiotics alone account for the dramatic diminution in first attacks of ARF in the us. The decrease in incidence of ARF actually began prior to the antibiotic era (12, l3). Moreover, the paucity of medical resources in urban poverty pockets makes it unlikely that most children with a self-limited illness such as acute streptococcal pharyngitis will receive appropriate treatment. Finally, one third or more of cases of ARF occur after asymptomatic throat infections with the group A streptococcus, and such cases thus do not come to medical attention at a time when prevention is possible. This is illustrated by the Baltimore experience, in which the establishment of inner city comprehensive health care programs for children and adolescents suc ceeded in reducing first attacks of ARF by half in patients with preceding clinical respiratory infection but did not affect the rate of occurrence of such attacks in individuals whose antecedent infection was asymptomatic (14). Could the prevalence of group A streptococci be decreasing or are currently prevalent strains incapable of initiating pharyngeal infection? Although precise data are lacking, there is no reason to believe this is true. Pediatricians and family practitioners continue to see cases of exudative pharyngitis from which Streptococcus pyogenes is isolated in profusion (15). The percentage of positive cultures did not change appreciably in a pediatric practice in Rochester, New York, between 1967 and 1982 (16). Other possible explanations include a change in the intrinsic sus ceptibility of the human host to the development of ARF or a diminution in the rheumatogenic potential of group A streptococcal strains. The former is unlikely, because the time course of the decline, occurring over a period of decades, is too brief to allow a major change in genetic constitution of the host. On the other hand, a substantial body of data suggests that group A streptococcal strains may vary in their ability to elicit ARF and that strains prevalent in most US communities in recent years have not been highly rheumatogenic (17, 18, 18a).
Rheumatogenic Group A Streptococci Epidemiologic evidence suggesting the existence of rheumatogenic and nonrheumatogenic streptococci includes the marked temporal and geo graphic variability in the incidence of ARF in temperate climates and
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the fact that the two nonsuppurative sequelae of group A streptococcal infection, ARF and post-streptococcal acute glomerulonephritis (AGN), rarely occur simultaneously in the same patient (19). Reports from the 1940s clearly document institutional outbreaks of streptococcal phar yngitis that failed to elicit ARF (20) or even to reactivate the disease in highly susceptible rheumatic patients (21). Analysis of epidemics of ARF reveals that certain streptococcal M-protein serotypes are strongly and repetitively implicated while other equally prevalent M-types havc rarely, if ever, been associated with the disease (22). Although the association of particular serotypes with ARF is much more difficult to ascertain in endemically occurring disease, reports from Trinidad (23, 24), New Zealand (25), Kuwait (26), and Chile (27, 28) suggest differences in the streptococcal types causing ARF and AGN in the same populations. In the Chilean studies (28) there was bacteriologic and immunologic evidence of infection with M-type 5, a highly rheumatogenic serotype, in many of the patients with ARF. Detailed studies of the M -protein molecule reveal a possible theoretical basis for the relationship of M-type to rheumatogenicity. There are distinct structural differences between the M-proteins of rheumatogenic and nephritogenic streptococci (29). Moreover, M-proteins of the group A streptococcal serotypes most strongly epidemiologically associated with ARF share a particular surface-exposed antigenic domain (30). Of equal interest has been the recognition that certain epitopes are held in common between M-protein molecules of highly rheumatogenic streptococci and human heart tissue. Cross-reactions have been documented with sarco lemmal membrane proteins (31) and cardiac myosin (32). The foregoing data thus indicate that group A streptococci vary in their capacity to initiate ARF and that, as with nephritogenicity, rheumato genicity is highly correlated with M-protein serotype. There are, how ever, many remaining questions. Is rheumatogenicity a relative or an absolute characteristic of group A streptococci? Are all strains of rheu matogenic serotypes equally rheumatogenic? Are certain serotypes both rheumatogenic and nephritogenic? This appears to be true for types 1 and 3. If so, are there individual strains of these serotypes with the ability to initiate both sequelae (19)'1 One other biologic feature of certain rheumatogenic streptococci should be noted. Clinicians and medical microbiologists have long observed that the presence of mucoid colonies of group A stretptococci in throat cultures often presaged the appearance of cases of ARF (33). Such colonies indicate that the infecting streptococci produce abundant amounts of capsular hyaluronate. In recent years such mucoid strains have rarely been isolated from pharyngeal infections.
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The Resurgence of Rheumatic Fever The past five years have witnessed a remarkable and unanticipated resurgence of ARF in the United States. Beginning in early 1985, an epidemic of the disease occurred in Salt Lake City, Utah, and in the surrounding intermountain area (4). By June of 1986, 74 cases had been admitted to the Primary Children's Medical Center in Salt Lake City. This represented an eight-fold increase over the annual number of ARF cases diagnosed during the preceding decade. Smaller clusters, ranging from 17 to 40 cases, were reported during approximately the same time period from Columbus (34) and Akron, Ohio (35), and from Pittsburgh, Pennsyl vania (36). The incidence of carditis reported in these outbreaks ranged from 30 to 72% . Moreover, clinicians in many other parts of the country began seeing occasional cases of ARF, a disease that had been absent from their hospital wards for years. A survey by the Centers for Disease Control (37) identified a two-fold or greater increase in ARF incidence in 6 of 24 states conducting passive surveillance for ARF. As startling as the return of rheumatic fever was the epidemiologic pattern it presented. No longer was the disease concentrated in urban poverty pockets. Rather, its victims were predominantly white, middle class children who lived in suburban or rural settings (Table 1). In the Utah outbreak, for example, 96% of the patients were white (reflecting the demographics of the state), and the average annual income in a sample of 50 affected families was $34,000, a full $ 10,000 higher than the mean family income in Utah as a whole (4). In the heyday of rheumatic fever, the disease was the bane of military recruit camps. During World War II, for example, the incidence of rheu matic fever in military camps varied from 43 per 1 00,000 among soldiers stationed in the southeastern United States to 388 per 100,000 in the northeast (38). Indeed, the problem was severe enough to require the routine administration of intramuscular benzathine penicillin G to incoming recruits. By the 1980s, such problems were thought to be of historical interest only. Between December 1986 and July 1987, however, the Naval Training Center (NTC) in San Diego, California, which had abandoned benzathine penicillin G prophylaxis in 1980, experienced an epidemic of acute streptococcal pharyngitis punctuated by 10 cases of ARF (39). The ARF attack rate among recruits at NTC, which had been below 1 per 1 00,000 for the preceding five years, was 80 per 1 00,000 during 1987. No cases of ARF occurred at the San Diego Marine Corps Recruit Depot, which is adjacent to NTC and has continued to administer benza thine penicillin G prophylaxis. A second military outbreak occurred at the Fort Leonard Wood,
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Table 1
Recently reported civilian outbreaks of ARF: selected epidemiologic features
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Time
Salt Lake
Columbus
Akron
Pittsburgh
City (34)
(35)
(36)
(37)
1/85-6/86
6/84--9/86
1986
1985-1986
Number of cases
74
40
23
17
White (%)
96
90
96
94
Family income
$34,000
73% Middle
$20,000-
3 of 17 on
$40,000
assistance
Suburban-rural
-
85%
Many
75%
residents History of sore
33
55
78
24
5
39
64
30
59
throat (%) Family history of rheumatic fever (%) Recurrences (%) Carditis (%)
4
2.5
72
50
M-lypes of group A streptococci isolated from 1, 5, 18
Patients Families Community
3, I, 18, ?78 Mucoid MUl
6 Mucoid MI8
6, 5, 11, 9, 12 •
Not reported or negative.
Missouri, army training base between February 1987 and February 1988 (40). Ten soldiers developed ARF at Fort Leonard Wood and five addi tional recruits developed the disease within five weeks of transfer to other army posts. The Fort Leonard Wood outbreak terminated after reinstitu tion of intramuscular prophylaxis with benzathine penicillin G. A number of streptococcal strains have been isolated from ARF patients and their family contacts in the reported civilian outbreaks (Table 1) and from sporadically occurring cases elsewhere in the US (4 1). These isolates include representatives of a variety of serotypes that have been epide miologically associated with the disease in the past (e.g. types 1 , 3, 5, 6 and 18). Of particular interest is M-type 18. To the author's knowledge, this serotype has rarely been isolated from domestic sources in recent years. It was, however, the cause of an outbreak of AR F in military recruits at Lowry Air Force Base in Colorado in the late 1960s (42). Tn addition to being isolated from ARF patients and their family contacts in various locales, M-type 18 was found to be highly prevalent both in Utah at the
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time of the epidemic there (4) and in surveys carried out in Columbus, Ohio, during 1986- 1987 (43). Finally, of 85 group A streptococci isolated from throats of soldiers at Fort Leonard Wood, 74% were M-type 18. A striking feature of most strains of M-type 18 is their mucoid colonial morphology. The mucoid nature of the prevalent streptococcal strains was apparent in the Utah and Columbus outbreaks as well. Indeed, a high proportion of the rheumatogenic strains of various types examined by Kaplan et al (4 1) from ARF patients and their siblings were mucoid. The reappearance of highly encapsulated streptococcal strains of purportedly rheumatogenic serotypes has been accompanied by reports of unusually severe pyogenic infections. During the San Diego NTC outbreak, for example, six cases of pneumonia and one case of septic arthritis due to the group A streptococcus occurred. Moreover, there have been several reports of a toxic-shock-like syndrome due to the group A streptococcus (44severity, similar to descriptions of certain streptococcal infections in the
pre-antibiotic era. Many of the strains associated with the "toxic strep syndrome" produce streptococcal pyrogenic exotoxin A, a type of erythrogenic toxin that has been quite rare among disease-producing strep tococci isolated in recent years (47).
Lessons from the Resurgence The reasons for the resurgence of ARF in the mid- 1980s and for its atypical epidemiologic behavior remain obscure. The occurrence of ARF outbreaks in middle-class suburbs calls strongly into question the assumptions that the steep decline in ARF incidence in the period 1960- 1985 was due exclusively to improvements in living standards or to ready access to medical care. The defects in our strategy of primary prevention, based upon precise diagnosis and appropriate antimicrobial therapy of streptococcal pharyngitis, are clearly exposed. This approach is undoubtedly efficacious in preventing cases of ARF and perhaps in decreasing the interpersonal transmission of virulent streptococci. It cannot, however, protect those children whose attack of ARF follows a clinically asymptomatic phar yngeal infection (Table 1). Finally, the recent resurgence provides further evidence of the relative rheumatogenicity of group A streptococci and confirms the observations that certain bacteriologic and serotypic char acteristics are highly correlated with the ability of a strain to elicit rheu matic fever. We still do not know whether rheumatogenicity is simply a reflection of strain virulence or whether, as the emerging structural data might suggest, there is a specific rheumatogenic antigenic configura tion.
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Implications for the Clinician and the Investigator During the years when ARF was prevalent in the United States, primary care physicians adopted rather stringent methods of management of strep tococcal pharyngitis, which included treatment of culture-positive patients with intramuscular benzathine penicillin G, posttreatment follow-up throat cultures to ensure eradication of the infecting strain, and a repeat course of therapy if group A streptococci persisted. Many practitioners also cultured family contacts, even if asymptomatic, and treated with penicillin those whose cultures were positive. As ARF became pro gressively less common, management strategies became more lax. Intra muscular benzathine penicillin G, which provided adequate therapy in a single injection, gave way in most practices to 1 0 days of oral penicillin V. Although the latter is better accepted by patients and parents, compliance is extremely difficult to ensure once the acute symptoms subside. Given the low risk of ARF and the fact that a high proportion of patients failing treatment are streptococcal carriers rather than acutely infected individuals (48), the American Heart Association (49) currently recommends post treatment cultures "only in patients who are at unusually high risk for rheumatic fever, who remain symptomatic, or who develop recurring symptoms." The American Heart Association likewise discourages routine culture and treatment of asymptomatic family contacts, except when the risk of ARF is deemed to be particularly high. It is unclear whether the outbreaks and sporadic cases of ARF occurring in recent years presage a full-scale return of the disease to levels seen in the 1950s and 1960s. The resurgence remains spotty, and the incidence of ARF is still quite low in many areas of the country. Strategies for man agement of streptococcal pharyngitis, therefore, must at the present time be individualized to a certain extent, depending on the perceived risk of ARF in the community and family unit under consideration. The reader is referred to other sources (e.g. 50) for a consideration of the relative merits of throat culture vs direct antigen testing for identification of group A streptococci in the pharynx. The sine qua non, however, is careful clinical and bacteriologic assessment of patients with acute pharyngitis, particularly in the pediatric and adolescent age groups, and appropriate antimicrobial therapy of individuals positive for group A streptococci. Careful epidemiologic surveillance of military installations is necessary to determine thresholds of streptococcal disease that should trigger mass prophylaxis with benzathine penicillin G in such a setting. Biomedical investigators obviously have much to learn about the factors involved in herd immunity and strain variability that allow the cyclical emergence of rheumatogenic streptococci. Moreover, there is now great
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interest, intensified by the resurgence of ARF in the US, in the development of vaccines directed against strains of the major rheumatogenic M-protein serotypes (51). The approach is logical, because M-protein is the major virulence factor of the organism, and acquired immunity to group A streptococcal infection is known to be M-type specific. Any such vaccine, however, would have to be scrupulously freed from epitopes cross-reactive with human heart. Finally, there is epidemiologic and experimental evidence suggestive of a genetic predisposition to the development of ARF. The disease is known to cluster in families. For example, 39 and 64% of ARF patients in the Akron and Pittsburgh outbreaks, respectively, had a family history of the disease. Certain class II human histocompatibility antigens are encoun tered significantly more frequently in ARF patients than in controls (52). Recent studies indicate that rheumatic subjects express a particular sur face antigen on their B cells to a much greater extent than do normal controls (53). Whether such expression is due to genetic or acquired influ
ences, or perhaps to a combination of the two, remains to be ascertained. An ultimate goal of current streptococcal research would be to devise a safe, highly immunogenic vaccine conferring immunity to rheumatogenic group A streptococcal serotypes and to administer the vaccine to those individuals whose genetic constitution predisposes them to the devel opment of ARF. From our present vantage point, such a goal remains distant but by no means unattainable.
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23. Potter, E. V., Svartman, M., Poon-King, T., Earle, D. P. 1977. The families of patients with acute rheumatic fever or glomerulonephritis in Trinidad. Am. J. Epidemiol. 106: 130-38 24. Potter, E. V., Svartman, M., Mohammed, I., Cox, R., Poon-King, T., et al. 1978. Tropical acute rheumatic fever and asso ciated streptococcal infections com pared with concurrent acute glomerulo nephritis. J. Pediatr. 92: 325-33 25. Lennon, D., Martin, D., Wong, E., Taylor, L. R. 1988. Longitudinal study of poststreptococcal disease in Auck land; rheumatic fever, glom erulo neph ri tis, cpidemiology and M-typing 198186. NZ Med.J. 101 : 396-98 26. Majeed, H. A., Khuffash, F. A., Mohsen, A., Farwana, S. S., Chugh, T. D., el a!. 1988. The rheumatogenic and nephritogenic strains of the group A streptococcus: the Kuwait experience. NZ Med.J. 101: 398-401 27. Berrios, X., Quesney, F., Morales, A., B1azquez, 1., Lagomarsino, E., et al. 1986. Acute rheumatic fever and post streptococcal glomerulonephritis in an open population: comparative studies of epidemiology and bacteriology. J. Lab. Clin. Med. 108: 535-42. 28. Bisno, A. L., Berrios, X., Quesney, F., Monroe, D. M. Jr., Dale, J. B., et al. 1982. Type-specific antibodies to struc turally defined fragments of strepto coccal M-proteins in patients with acute rheumatic fever. Infec. Immun. 38: 57379 29. Khandke, K. M., Fairwell, T., Manjula, B. N. 1987. Differ enc e in the structural features of streptococcal M-proteins from nephritogenic and rheumatogenic serotypes. J. Exp. Med. 166: 15162 30. Bessen, D., Jones, K. F., Fischetti, V. A. 1989. Evidence for two distinct classes of streptococcal M-protein and their relationship 10 rheumatic fever. J. Exp. Med. 169: 269-83 31. Dale, 1. B., Beachey, E. H. 1982. Pro tective antigenic determinant of strep tococcal M-protein shared with sarco lemmal membrane protein of human heart. J. Exp. Med. 156: 1165-76 32. Dale, J. B., Beachey, E. H. 1985. Epitopes of streptococcal M-proteins shared with cardiac myosin. J. Exp. Med. 162: 583-91 33. Stollerman, G. H. 1975. The relative rheumatogenicity of strains of group A streptococci. Mod. Concepts Cardiovasc. Dis. 44: 35-40 34. Hosier, D. M., Craenen, J. M., Teske, D. W., Wheller, J. J. 1987. Resurgence
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40. Centers for Disease Control. 1988. Acute rheumatic fever among army trainees-Fort Leonard Wood, Mis souri, 1987-1988. Morb. Mortal. Wkly. Rep. 37: 519-22 41. Kaplan, E. L., Johnson, D. R., Cleary, P. P. 1989. Group A streptococcal sero types isolated from patients and sibling contacts during the resurgence of rheu matic fever in the United States in the mid-1980s. J. Infect. Dis. 159: 101-3 42. James, L., McFarland, R. B. 1971. An epidemic of pharyngitis due to a non hemolytic group A streptococcus at Lowry Air Fo rce Base. N. Engl. J. Med. 284: 750-52 43. Marcon, M. J., Hribar, M. M., Hosier, D. M., Powell, D. A., Brady, M. T., et al. 1988. Occurrence of mucoid M-18 Streptococcus pyogenes in a central Ohio pediatric population. J. Clin. Microbiol. 26: 1539-42 44. Bartter, T., Dascal, A., Carroll, K., Curley, F. J. 1988. 'Toxic Strep Syn drome': A manifestation of group A streptococcal infection. Arch. Intern.
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Med. 148: 1421-24 45. Cone, L. A., Woodard, D. R., Schliever(, P. M., Tomory, G. S. 1987. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N. Engl. J. Med. 317: 146-49 46. Stollerman, G. H. 1988. Changing group A streptococci: The reappearance of streptococcal "toxic shock". Arch. Intern. Med. 148: 1268-70 47. Stevens, D. L., Tanner, M. H., Winship, J., Swarts, R., Ries, K. M., et al. 1989. Severe group A streptococcal infections associated with a toxic shock-like syn drome and scarlet fever toxin A. N. Engl. J. Med. 321: 1-7 48. Kaplan, E. L., Gustanaduy, A. S., Huwe, B. W. 1981. The role of the carrier in treatment failures after antibiotic therapy for group A streptococci in the upper respiratory tract. J. Lab. CUn. Med. 98: 326-35
49. Committee
50.
51.
52.
53.
on
Rheumatic
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fective Endocarditis, and Kawasaki Disease, American Heart Association. 1988. Prevention of rheumatic fever. Cir culation 78: 1082-86 Kellogg, J. A., Manzella, J. P. 1986. Detection of group A streptococci in the laboratory or physician's office. J. Am. Med. Assoc. 255: 2638-42 Beachey, E. H., Stollerman, G. H., John son, R. H., Ofek, I., Bisno, A. L. 1979. Human immune response to immuniz ation with a structurally-defined polypep tide fragment of streptococcal M-pro tein. J. Exp. Med. 150: 862-77 Ayoub, E. M., Barrett, D. J., Maclaren, N. K., Krischer, J. P. 1986. Association of class II human histocompatibility leu kocyte antigens with rheumatic fever. J. Clin. Invest. 77: 2019-26 Khanna, A. K., Buskirk, D. R., Williams, R. C. Jr., Gibofsky, A., Crow, M. K., et al. 1989. Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J. CUn. Invest. 83: 1710-16
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THE RESURGENCE OF ACUTE Annu. Rev. Med. 1990.41:319-329. Downloaded from www.annualreviews.org Access provided by University of California - San Francisco UCSF on 01/28/15. For personal use only.
RHEUMATIC FEVER IN THE UNITED STATESl Alan L. Bisno, M.D. Medical Service, Miami Veterans Administration Medical Center, Miami, Florida 33125; and Departm ent of Medi cin e ,
University of Miami School of Medicine, Miami, Florida KEY WORDS:
streptococcus group A, heart disease, epidemiology, disease prevention, streptococcal pharyngitis.
ABSTRACT
The incidence of acute rheumatic fever (ARF) had been decl i ning in t he United States for decades, and by the late 1970s ARF had become a rare disease in most areas of the country. The mid-1980s saw a resurgence of ARF, with reported outbreaks in Utah, Ohio, Pennsylvania, and military recruit camps in Missouri and California, as well as sporadic cases in many other communities. This review summarizes salient epidemiologic data related to the resurgence, explores some possible explanations for its occur
rence, and discusses strategies for prevention of rheumatic fever now and in the future. INTRODUCTION Since the end of World War II, there has been a dramatic decline in the in ciden ce of acute rheumatic fever (ARF) in the United States. This decline
is readily apparent in the closure or reassignment of the famous rheu matic fever sanitaria (e.g. Irvington House outside New York City, La Rabida in Chicago, House of the Good Samaritan in Boston) and in the I
The US Government has the right to retain a nonexclusive, royalty-free license in and to
any copyright covering this paper.
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unfamiliarity of younger physicians with the clinical manifestations of the disease. The magnitude of t he decline can be documented more precisely in selected geographic locales where reliable sequential data are available. For example, the incidence of ARF among school-aged children in Rochester, Minnesota, decreased from 65 per 100,000 in 1935-1949 to 41 in 1950-1964 to 9 in 1965-1978
(1).
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In the quarter century between 1960 and 1985, the rate of decline was particularly steep. The annual incidence (hospitalized cases only) of ARF among persons aged 5 to 19 years in Baltimore, Maryland, plummeted from 15.6 per 100,000 in 1960-1964 to approximately 0.5 in 1977-1981
(2, 3). Similar extremely low incidence figures have been reported in recent years by investigators from Rhode Island to California (4). In a careful, community-wide survey conducted by the author and colleagues in Memphis-Shelby County, Tennessee, the incidence of ARF among school-aged children during 1977-1981 was 1.88 per 100,000 overall and only 0.5 in the more affluent suburbs. The latter finding prompted us to describe ARF in the early 1980s as "a vanishing disease in suburbia"
(5).
The virtual disappearance of ARF as a significant public health problem is not unique to the United States. Similar trends are apparent in the major wcstern industrialized countries and in Asia as well (6, 7). In contrast, ARF continues to be among the most important causes of cardiovascular morbidity and mortality in the Indian subcontinent, the Arab countries of the Middle East, and many other developing nations of the world. In Sri Lanka in 1978, for example, the morbidity rate of ARF was 47 per 100,000 for the population as a whole and over 140 for those aged 5 to 19 years (8). At the medical college in Allahabad, India, rheumatic heart disease accounts for approximately 40% of cardiac admissions, a proportion that remained essentially constant between 1966 and 1980 (9).
What Caused the Decline in Rheumatic Fever? There has been intense speculation as to the reasons for the dramatic decline in ARF incidence in the US and other highly industrialized coun tries. Several factors have been pinpointed, but none appears sufficient by itself to explain the phenomenon. The first factor is an improvement in the general standard of living. Certainly, ARF tends to thrive on poverty. This is true not only on a global basis but even in individual communities. In the US, for example, ARF incidence is much lower among affluent, usually Caucasian, populations than in the impoverished black or Hispanic ghettos of our urban metropolises
(2, 5, 10). The link between socio
economic status and ARF incidence is unexplained. It could be related to factors such as nutrition, hygiene, and access to medical care. One critical
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variable, however, may be household and bedroom crowding, conditions known to predispose to the interpersonal transmission of group A strep tococci (11). Clearly, penicillin played a significant role in the post-World War II decline in ARF morbidity and mortality, particularly in preventing recur rences of the disease. It is unlikely however, that antibiotics alone account for the dramatic diminution in first attacks of ARF in the us. The decrease in incidence of ARF actually began prior to the antibiotic era (12, l3). Moreover, the paucity of medical resources in urban poverty pockets makes it unlikely that most children with a self-limited illness such as acute streptococcal pharyngitis will receive appropriate treatment. Finally, one third or more of cases of ARF occur after asymptomatic throat infections with the group A streptococcus, and such cases thus do not come to medical attention at a time when prevention is possible. This is illustrated by the Baltimore experience, in which the establishment of inner city comprehensive health care programs for children and adolescents suc ceeded in reducing first attacks of ARF by half in patients with preceding clinical respiratory infection but did not affect the rate of occurrence of such attacks in individuals whose antecedent infection was asymptomatic (14). Could the prevalence of group A streptococci be decreasing or are currently prevalent strains incapable of initiating pharyngeal infection? Although precise data are lacking, there is no reason to believe this is true. Pediatricians and family practitioners continue to see cases of exudative pharyngitis from which Streptococcus pyogenes is isolated in profusion (15). The percentage of positive cultures did not change appreciably in a pediatric practice in Rochester, New York, between 1967 and 1982 (16). Other possible explanations include a change in the intrinsic sus ceptibility of the human host to the development of ARF or a diminution in the rheumatogenic potential of group A streptococcal strains. The former is unlikely, because the time course of the decline, occurring over a period of decades, is too brief to allow a major change in genetic constitution of the host. On the other hand, a substantial body of data suggests that group A streptococcal strains may vary in their ability to elicit ARF and that strains prevalent in most US communities in recent years have not been highly rheumatogenic (17, 18, 18a).
Rheumatogenic Group A Streptococci Epidemiologic evidence suggesting the existence of rheumatogenic and nonrheumatogenic streptococci includes the marked temporal and geo graphic variability in the incidence of ARF in temperate climates and
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the fact that the two nonsuppurative sequelae of group A streptococcal infection, ARF and post-streptococcal acute glomerulonephritis (AGN), rarely occur simultaneously in the same patient (19). Reports from the 1940s clearly document institutional outbreaks of streptococcal phar yngitis that failed to elicit ARF (20) or even to reactivate the disease in highly susceptible rheumatic patients (21). Analysis of epidemics of ARF reveals that certain streptococcal M-protein serotypes are strongly and repetitively implicated while other equally prevalent M-types havc rarely, if ever, been associated with the disease (22). Although the association of particular serotypes with ARF is much more difficult to ascertain in endemically occurring disease, reports from Trinidad (23, 24), New Zealand (25), Kuwait (26), and Chile (27, 28) suggest differences in the streptococcal types causing ARF and AGN in the same populations. In the Chilean studies (28) there was bacteriologic and immunologic evidence of infection with M-type 5, a highly rheumatogenic serotype, in many of the patients with ARF. Detailed studies of the M -protein molecule reveal a possible theoretical basis for the relationship of M-type to rheumatogenicity. There are distinct structural differences between the M-proteins of rheumatogenic and nephritogenic streptococci (29). Moreover, M-proteins of the group A streptococcal serotypes most strongly epidemiologically associated with ARF share a particular surface-exposed antigenic domain (30). Of equal interest has been the recognition that certain epitopes are held in common between M-protein molecules of highly rheumatogenic streptococci and human heart tissue. Cross-reactions have been documented with sarco lemmal membrane proteins (31) and cardiac myosin (32). The foregoing data thus indicate that group A streptococci vary in their capacity to initiate ARF and that, as with nephritogenicity, rheumato genicity is highly correlated with M-protein serotype. There are, how ever, many remaining questions. Is rheumatogenicity a relative or an absolute characteristic of group A streptococci? Are all strains of rheu matogenic serotypes equally rheumatogenic? Are certain serotypes both rheumatogenic and nephritogenic? This appears to be true for types 1 and 3. If so, are there individual strains of these serotypes with the ability to initiate both sequelae (19)'1 One other biologic feature of certain rheumatogenic streptococci should be noted. Clinicians and medical microbiologists have long observed that the presence of mucoid colonies of group A stretptococci in throat cultures often presaged the appearance of cases of ARF (33). Such colonies indicate that the infecting streptococci produce abundant amounts of capsular hyaluronate. In recent years such mucoid strains have rarely been isolated from pharyngeal infections.
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The Resurgence of Rheumatic Fever The past five years have witnessed a remarkable and unanticipated resurgence of ARF in the United States. Beginning in early 1985, an epidemic of the disease occurred in Salt Lake City, Utah, and in the surrounding intermountain area (4). By June of 1986, 74 cases had been admitted to the Primary Children's Medical Center in Salt Lake City. This represented an eight-fold increase over the annual number of ARF cases diagnosed during the preceding decade. Smaller clusters, ranging from 17 to 40 cases, were reported during approximately the same time period from Columbus (34) and Akron, Ohio (35), and from Pittsburgh, Pennsyl vania (36). The incidence of carditis reported in these outbreaks ranged from 30 to 72% . Moreover, clinicians in many other parts of the country began seeing occasional cases of ARF, a disease that had been absent from their hospital wards for years. A survey by the Centers for Disease Control (37) identified a two-fold or greater increase in ARF incidence in 6 of 24 states conducting passive surveillance for ARF. As startling as the return of rheumatic fever was the epidemiologic pattern it presented. No longer was the disease concentrated in urban poverty pockets. Rather, its victims were predominantly white, middle class children who lived in suburban or rural settings (Table 1). In the Utah outbreak, for example, 96% of the patients were white (reflecting the demographics of the state), and the average annual income in a sample of 50 affected families was $34,000, a full $ 10,000 higher than the mean family income in Utah as a whole (4). In the heyday of rheumatic fever, the disease was the bane of military recruit camps. During World War II, for example, the incidence of rheu matic fever in military camps varied from 43 per 1 00,000 among soldiers stationed in the southeastern United States to 388 per 100,000 in the northeast (38). Indeed, the problem was severe enough to require the routine administration of intramuscular benzathine penicillin G to incoming recruits. By the 1980s, such problems were thought to be of historical interest only. Between December 1986 and July 1987, however, the Naval Training Center (NTC) in San Diego, California, which had abandoned benzathine penicillin G prophylaxis in 1980, experienced an epidemic of acute streptococcal pharyngitis punctuated by 10 cases of ARF (39). The ARF attack rate among recruits at NTC, which had been below 1 per 1 00,000 for the preceding five years, was 80 per 1 00,000 during 1987. No cases of ARF occurred at the San Diego Marine Corps Recruit Depot, which is adjacent to NTC and has continued to administer benza thine penicillin G prophylaxis. A second military outbreak occurred at the Fort Leonard Wood,
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Table 1
Recently reported civilian outbreaks of ARF: selected epidemiologic features
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Time
Salt Lake
Columbus
Akron
Pittsburgh
City (34)
(35)
(36)
(37)
1/85-6/86
6/84--9/86
1986
1985-1986
Number of cases
74
40
23
17
White (%)
96
90
96
94
Family income
$34,000
73% Middle
$20,000-
3 of 17 on
$40,000
assistance
Suburban-rural
-
85%
Many
75%
residents History of sore
33
55
78
24
5
39
64
30
59
throat (%) Family history of rheumatic fever (%) Recurrences (%) Carditis (%)
4
2.5
72
50
M-lypes of group A streptococci isolated from 1, 5, 18
Patients Families Community
3, I, 18, ?78 Mucoid MUl
6 Mucoid MI8
6, 5, 11, 9, 12 •
Not reported or negative.
Missouri, army training base between February 1987 and February 1988 (40). Ten soldiers developed ARF at Fort Leonard Wood and five addi tional recruits developed the disease within five weeks of transfer to other army posts. The Fort Leonard Wood outbreak terminated after reinstitu tion of intramuscular prophylaxis with benzathine penicillin G. A number of streptococcal strains have been isolated from ARF patients and their family contacts in the reported civilian outbreaks (Table 1) and from sporadically occurring cases elsewhere in the US (4 1). These isolates include representatives of a variety of serotypes that have been epide miologically associated with the disease in the past (e.g. types 1 , 3, 5, 6 and 18). Of particular interest is M-type 18. To the author's knowledge, this serotype has rarely been isolated from domestic sources in recent years. It was, however, the cause of an outbreak of AR F in military recruits at Lowry Air Force Base in Colorado in the late 1960s (42). Tn addition to being isolated from ARF patients and their family contacts in various locales, M-type 18 was found to be highly prevalent both in Utah at the
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time of the epidemic there (4) and in surveys carried out in Columbus, Ohio, during 1986- 1987 (43). Finally, of 85 group A streptococci isolated from throats of soldiers at Fort Leonard Wood, 74% were M-type 18. A striking feature of most strains of M-type 18 is their mucoid colonial morphology. The mucoid nature of the prevalent streptococcal strains was apparent in the Utah and Columbus outbreaks as well. Indeed, a high proportion of the rheumatogenic strains of various types examined by Kaplan et al (4 1) from ARF patients and their siblings were mucoid. The reappearance of highly encapsulated streptococcal strains of purportedly rheumatogenic serotypes has been accompanied by reports of unusually severe pyogenic infections. During the San Diego NTC outbreak, for example, six cases of pneumonia and one case of septic arthritis due to the group A streptococcus occurred. Moreover, there have been several reports of a toxic-shock-like syndrome due to the group A streptococcus (44severity, similar to descriptions of certain streptococcal infections in the
pre-antibiotic era. Many of the strains associated with the "toxic strep syndrome" produce streptococcal pyrogenic exotoxin A, a type of erythrogenic toxin that has been quite rare among disease-producing strep tococci isolated in recent years (47).
Lessons from the Resurgence The reasons for the resurgence of ARF in the mid- 1980s and for its atypical epidemiologic behavior remain obscure. The occurrence of ARF outbreaks in middle-class suburbs calls strongly into question the assumptions that the steep decline in ARF incidence in the period 1960- 1985 was due exclusively to improvements in living standards or to ready access to medical care. The defects in our strategy of primary prevention, based upon precise diagnosis and appropriate antimicrobial therapy of streptococcal pharyngitis, are clearly exposed. This approach is undoubtedly efficacious in preventing cases of ARF and perhaps in decreasing the interpersonal transmission of virulent streptococci. It cannot, however, protect those children whose attack of ARF follows a clinically asymptomatic phar yngeal infection (Table 1). Finally, the recent resurgence provides further evidence of the relative rheumatogenicity of group A streptococci and confirms the observations that certain bacteriologic and serotypic char acteristics are highly correlated with the ability of a strain to elicit rheu matic fever. We still do not know whether rheumatogenicity is simply a reflection of strain virulence or whether, as the emerging structural data might suggest, there is a specific rheumatogenic antigenic configura tion.
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Implications for the Clinician and the Investigator During the years when ARF was prevalent in the United States, primary care physicians adopted rather stringent methods of management of strep tococcal pharyngitis, which included treatment of culture-positive patients with intramuscular benzathine penicillin G, posttreatment follow-up throat cultures to ensure eradication of the infecting strain, and a repeat course of therapy if group A streptococci persisted. Many practitioners also cultured family contacts, even if asymptomatic, and treated with penicillin those whose cultures were positive. As ARF became pro gressively less common, management strategies became more lax. Intra muscular benzathine penicillin G, which provided adequate therapy in a single injection, gave way in most practices to 1 0 days of oral penicillin V. Although the latter is better accepted by patients and parents, compliance is extremely difficult to ensure once the acute symptoms subside. Given the low risk of ARF and the fact that a high proportion of patients failing treatment are streptococcal carriers rather than acutely infected individuals (48), the American Heart Association (49) currently recommends post treatment cultures "only in patients who are at unusually high risk for rheumatic fever, who remain symptomatic, or who develop recurring symptoms." The American Heart Association likewise discourages routine culture and treatment of asymptomatic family contacts, except when the risk of ARF is deemed to be particularly high. It is unclear whether the outbreaks and sporadic cases of ARF occurring in recent years presage a full-scale return of the disease to levels seen in the 1950s and 1960s. The resurgence remains spotty, and the incidence of ARF is still quite low in many areas of the country. Strategies for man agement of streptococcal pharyngitis, therefore, must at the present time be individualized to a certain extent, depending on the perceived risk of ARF in the community and family unit under consideration. The reader is referred to other sources (e.g. 50) for a consideration of the relative merits of throat culture vs direct antigen testing for identification of group A streptococci in the pharynx. The sine qua non, however, is careful clinical and bacteriologic assessment of patients with acute pharyngitis, particularly in the pediatric and adolescent age groups, and appropriate antimicrobial therapy of individuals positive for group A streptococci. Careful epidemiologic surveillance of military installations is necessary to determine thresholds of streptococcal disease that should trigger mass prophylaxis with benzathine penicillin G in such a setting. Biomedical investigators obviously have much to learn about the factors involved in herd immunity and strain variability that allow the cyclical emergence of rheumatogenic streptococci. Moreover, there is now great
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interest, intensified by the resurgence of ARF in the US, in the development of vaccines directed against strains of the major rheumatogenic M-protein serotypes (51). The approach is logical, because M-protein is the major virulence factor of the organism, and acquired immunity to group A streptococcal infection is known to be M-type specific. Any such vaccine, however, would have to be scrupulously freed from epitopes cross-reactive with human heart. Finally, there is epidemiologic and experimental evidence suggestive of a genetic predisposition to the development of ARF. The disease is known to cluster in families. For example, 39 and 64% of ARF patients in the Akron and Pittsburgh outbreaks, respectively, had a family history of the disease. Certain class II human histocompatibility antigens are encoun tered significantly more frequently in ARF patients than in controls (52). Recent studies indicate that rheumatic subjects express a particular sur face antigen on their B cells to a much greater extent than do normal controls (53). Whether such expression is due to genetic or acquired influ
ences, or perhaps to a combination of the two, remains to be ascertained. An ultimate goal of current streptococcal research would be to devise a safe, highly immunogenic vaccine conferring immunity to rheumatogenic group A streptococcal serotypes and to administer the vaccine to those individuals whose genetic constitution predisposes them to the devel opment of ARF. From our present vantage point, such a goal remains distant but by no means unattainable.
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