Rheumatic Fever. Y.S. Chandrashekhar and Jagat Narula. The Global Burden of Rheumatic Fever

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1 1 8 Rheumatic Fever Y.S. Chandrashekhar and Jagat Narula The Global Burden of Rheumatic Fever Etiopathogenesis Mechanisms of Damage Pathology Clinical Features Clinical Diagnosis Laboratory Investigations Natural History Treatment Streptococcal Vaccine Key Points Streptococcal group A β-hemolytic pharyngitis mediates acute rheumatic fever (ARF). Cardiac involvement in ARF involves pericardium, myocardium, and endocardium. The pathognomonic histopathologic finding in the myocardium is the Aschoff nodule. Arthritis is often the earliest manifestation of ARF and brings the patient to clinical attention. Carditis is the only manifestation of ARF that results in permanent deformity. Clinically detectable cardiac involvement occurs in a significant proportion of patients with ARF. Rheumatic fever (RF) is a delayed, noninfectious consequence of pharyngitis caused by group A β-hemolytic streptococci (GABHS). While it is rare in the developed world, RF remains a major problem worldwide. 1 However, RF still continues to show up unexpectedly even in the First World as evidenced by occasional outbreaks in the United States. 2 Furthermore, given the magnitude of international travel and immigration, clinicians everywhere are likely to encounter RF or its devastating cardiac sequelae. Finally, the cause of the rise and fall of RF in the developed world has not been fully explained at a time when GABHS carrier rates have not been significantly diminished. 3 This raises the possibility of a sudden, unexpected resurgence, and RF thus remains an important disease to understand. Acute rheumatic fever affects multiple organ systems, which makes it a difficult diagnosis in regular practice; most commonly it presents as a combination of arthritis, carditis, chorea, erythema marginatum, and/or subcutaneous nodules, and valvular heart disease remains a major long-term sequela. It has thus been aptly said that rheumatic fever licks the joints, but bites the heart. This chapter briefly discusses the pathogenesis, recognition, treatment, and prevention of acute RF. The reader is referred elsewhere 4 for more in-depth treatment of this topic. The Global Burden of Rheumatic Fever Acute RF (ARF) was a major problem in the U.S. until the 1960s, and in fact was a common cause of disqualification among young men and women being considered for the military. Since then, RF has largely disappeared as a major cause of illness in the U.S. 5 Improved socioeconomic status, reduced crowding, the advent of antibiotics, and the widespread treatment of streptococcal throat infections have contributed to this decline. Unfortunately, ARF continues to be rampant in the developing world. The World Health Organization (WHO) 6 reported an incidence of ARF of fewer than 1 case per 100,000 population per year in the industrialized world, compared to 100 to 150 cases per 100,000 population in some areas of the eastern Mediterranean, the western Pacific and China. Acute RF remains a cause of much morbidity in the young. Rheumatic heart disease (RHD), a long-term sequela of RF, continues to be the most common cause of cardiovascular complication and death in young persons in the developing countries. Surveys in school-age children show an RHD prevalence as high as 78 per 1000 in some developing countries. 7 It accounts for more than one third of cardiovascular admissions to hospitals in developing countries and constitutes a major indication for cardiac surgery. 8 Thus, RF and RHD impose a significant economic burden on the total health budget in developing countries. Having said that, RF continues to show up all over the world, and several outbreaks have occurred in the U.S. in portions of Utah and Ohio and at U.S. Naval Training Centers. 9 Many of these outbreaks have involved middleclass suburbs, less crowded communities, and people with access to excellent health care a situation entirely unlike the developing world, where socioeconomic issues are thought to be responsible for RF outbreaks. This once again emphasizes our limited understanding of RF. 431

2 432 chapter 18 Etiopathogenesis The pathogenesis of rheumatic fever and RF-induced cardiac damage is not well understood. The lack of a good clinical model for RF is an important limitation. However, there is a significant body of data to suggest an autoimmune process. The salient features involved in the pathogenesis include (1) a human host who harbors RF susceptibility factors, which are thought to increase the proclivity to developing ARF; (2) pharyngitis (and interestingly, not other sites of streptococcal infection) with certain strains of GABHS with rheumatogenic potential; (3) the presence of an immune response against specific streptococcal antigens; the magnitude of this response correlates with the occurrence of subsequent ARF; and (4) an interval of 1 to 5 weeks between GABHS pharyngitis and the development of ARF that presumably allows time for mounting an immune-mediated injury. Host Factors Only a few individuals with group A streptococcal infection develop RF, 10 and the genetic makeup of the host may convey differing susceptibility to ARF. The putative susceptibility factor remains unclear so far, and indeed there may be many such factors. Identifying these factors is likely to help us target preventive measures and is the focus of intense study. Certain racial characteristics (e.g., Samoans in Hawaii and Maori in New Zealand) and a history of previous episodes of RF increased the susceptibility to RF after GABHS pharyngitis. Another factor may be the differing ability to mount a vigorous antibody response since this correlates with the occurrence of ARF. Familial or genetic susceptibility to RF has been postulated. 11,12 Acute RF risk correlates with the increased prevalence of human leukocyte antigen (HLA) DR4 in the U.S. 12 and Saudi Arabia 13 and with the increased prevalence of DR3 and DQw2 in India. 14 However, these associations were obtained with older serologic methods and have to be confirmed with newer methods of typing. Some other markers, such as B-cell alloantigen D8/17, have shown a strong association with susceptibility to RF 15 in U.S. populations, but these perform less efficiently in North Indian populations where other markers seem to perform better. Finally, target organ sensitivity may also be genetically determined in rheumatic fever, and this kind of sensitivity may determine which tissues get deposited with antibodies. 16 Factors Within Streptococci Among the various serotypes of group A streptococci, only some appear more likely to initiate acute RF (M-types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29), whereas some other strains are not commonly associated with ARF (M2, 4, and 28). Furthermore, only throat and not skin infections mediate ARF. The exact mechanism by which GABHS initiates RF is unclear, and it is also not known why throat infections and not other streptococcal infections lead to RF. In general, the RF strains tend to be rich in M protein, provoke an intense M-type specific immune response, and probably share epitopes with human tissue. However, the concept of rheumatogenic streptococci and the concept that only throat infection can cause ARF is not universally accepted 17 and awaits further study. Mechanisms of Damage Despite some claims of direct injury by streptococci, viruses, or toxins, most data suggest that RF is an autoimmune injury. Antibodies (cross-reactive and polyspecific) that react to shared antigens between streptococci and human tissue (molecular mimicry) are thought to underlie this process. Rheumatogenic streptococci contain multiple antigenic determinants that partially mimic normal human tissue antigens. 10 Thus the hyaluronate capsule, the streptococcal membrane, and the M-proteins share similarity with valve glycoproteins, myocardial sarcolemma, and cardiac contractile proteins, respectively. Following streptococcal pharyngitis, these antigens, which are recognized as foreign by the susceptible host, induce a hyperactive humoral and cellular immune response that damages native tissues bearing similar antigen. The type of damage is then partly the result of which tissue shows what kinds of mimicry. For example, antibodies to the N-acetylglucosamine moiety of group A polysaccharide cross-react with the heart valve tissue, 18 and this is thought to mediate valve damage; indeed such antibodies are increased in patients with rheumatic heart valve disease. 19 Breakdown of tolerance is an important component in the pathogenesis of ARF. The M-protein epitopes not only can trigger heart cross-reactive antibodies and T-cell responses 20 but also can act as superantigens. 21 This might explain the widespread immune response overriding the histocompatibility barrier. In fact, both humoral and cellular immune responses are more vigorous in patients with ARF than in normal subjects and might be related to superantigenic property of streptococcal M protein. A significant T- cell infiltration is also observed in the valvular tissue, and T cells isolated from valvular tissue of patients with rheumatic heart disease respond to streptococcal M5 protein and also cross-react with cardiac myosin. 22 This homology with cardiac myosin can be expected to decrease tolerance and may enhance T-cell mediated inflammatory damage. 23 Pathology The cardiac and noncardiac tissues differ in how they react to ARF. The inflammatory process in the skin, joints, and brain tends to regress spontaneously without any significant residual effects. There is swelling with serous effusion in the joints. Inflammatory infiltration and edema are evident in the synovial membranes. A fibrinoid exudates frequently lines the membranes. The blood vessels in the articular and periarticular areas are often inflamed and show infiltration with lymphocytes and polymorphonuclear leukocytes. On the other hand, the subcutaneous nodules have a center of fibrinoid necrosis with peripheral inflammatory reaction of lymphocytes and occasional polymorphonuclear leukocytes. Cardiac involvement in RF affects all three layers: pericardium, myocardium, and endocardium. The pericarditis is

3 rheumatic fever 433 A A B FIGURE (A,B) Pericarditis. Gross pathologic specimens obtained from a patient who died of rheumatic fever. The outer, or parietal, layer of the pericardium has been partially reflected away, revealing the epicardium, which is covered with shaggy fibrinous exudates as if a buttered sandwich had been pulled apart hence the term bread-and-butter pericarditis. B typically fibrinous (Fig. 18.1). The histopathologic findings in myocardium include the pathognomonic Aschoff nodule (Fig. 18.2). 24 The Aschoff granuloma consists of a central area of fibrinoid necrosis surrounded by cells of histiocyticmacrophage origin (Anitschkow cells), which show a typical owl s eye shaped nucleus. These cells are usually found in the subendocardial or perivascular regions in the myocardium. There is surprisingly little histopathologic damage to the myocardium, even in patients with florid clinical carditis and heart failure. 25,26 Myocyte necrosis is uncommon, and the cellular infiltrate is confined to the interstitium. This correlates with the lack of troponin leaks even in patients with frank rheumatic myocarditis. 27 The conduction system shows little pathology even in the presence of clinical conduction defects. The valves bear the brunt of the disease. The valves are inflamed and thickened during the acute stage of the rheumatic activity. The surface of the valves develops small, sterile vegetations or verrucae, particularly along the edges FIGURE (A) Low-power microscopic intramyocardial view shows Aschoff bodies. Note the nodular aggregate of Aschoff cells immediately adjacent to a coronary arteriole (Hematoxylin and eosin, 120). (B,C) High-power microscopic view of an Aschoff body illustrates the characteristic owl-and-caterpillar nuclei (H&E, 250). of the leaflets (Fig. 18.3), that are not associated with thromboembolic sequelae. A mild degree of inflammation leads to fusion of the cusps while more severe inflammatory reaction C

4 434 chapter 18 be gradual, and patients with acute RF may be seen without evidence of aortic valve affliction only to develop aortic regurgitation at a later date. Mitral and rarely aortic stenosis are late sequelae that result from scarring and inflammatory fusion of leaflet cusps. Clinical Features A B C FIGURE Valvulitis. (A) Gross appearance of the mitral valve shows characteristic tiny, wartlike verrucae or vegetations on its inflow side (atrial surface). (B) Similar verrucae on the ventricular surface of the aortic valve. The verrucae are sterile and small and only rarely result in embolization (unlike vegetations of bacterial endocarditis). (C) Microscopic appearance. extends into the subvalvular apparatus as well. This can result in early mitral or tricuspid regurgitation, caused partly by leaflet prolapse as well as annular dilatation. Aortic incompetence also occurs as a consequence of thickening and distortion of the valve leaflets. The scarring process may Joint Symptoms Arthritis is the earliest manifestation of RF and frequently brings the patient to clinical attention. 28 Arthritis occurs in at least two thirds of patients, and is more common in older patients. Although larger joints of the extremities are commonly involved, occasional involvement of smaller joints in the hand and feet may be seen; hips, spine, or axial joints are rarely affected. The joints are swollen, hot, red, and tender. The joints are inflamed at different times and for various intervals to impart a migratory character to joint pains. Monoarticular arthritis is not common. Arthritis usually resolves in 3 to 4 weeks even without treatment but responds instantly to aspirin therapy, and does not lead to permanent damage. Arthralgia without objective signs of inflammation is common in younger patients, in the presence of carditis, particularly in rheumatic recurrences and in RHD patients in the developing countries. 29 Some forms of polyarthritis after streptococcal pharyngitis may represent a reactive phenomenon. Poststreptococcal arthropathy is characterized by recurrent, severe, prolonged polyarthritis in adults that is not very responsive to nonsteroidal antiinflammatory agents. Although other manifestations of RF are not associated with arthropathy, some patients end up with residual heart disease. 30 Prophylaxis in reactive arthropathy remains similar to that for patients with RF, but very little data are available to provide definite recommendations. Cardiac Involvement Carditis is the only manifestation of RF that results in permanent deformity. 31 The cardiac involvement in RF has been reported to occur in nearly one third of almost all cases in various studies and in up to one half of cases in a prospective series. Clinical carditis was seen in 72% of patients in a resurgence of RF in Salt Lake City, 2 which is similar to the prevalence in the early part of the 20th century in the United States. 32 Subclinical carditis is being increasingly detected with modern imaging methods; evidence of valvular regurgitation was seen in 19% of additional cases with the use of echocardiography. Active rheumatic carditis can present in a number of ways, including subclinical cardiac involvement, acute or even fulminant congestive heart failure, and, occasionally, chronic ongoing carditis. Younger patients often present with carditis, whereas joint involvement is more common in older patients. 28 Although episodes of carditis occur less frequently in older patients, they present more often with unexplained worsening of congestive heart failure. The clinical findings may be suggestive of pericarditis, myocarditis, and valvulitis, and the guidelines for the diagnosis of rheumatic carditis are summarized in Table 18.1.

5 TABLE Simplified schema for the diagnosis of acute rheumatic carditis* rheumatic fever 435 Criteria First attacks Recurrences Valvulitis New onset apical systolic murmur or aortic regurgitation murmur Change in murmur Carey-Coombs murmur New-onset murmur Myocarditis Unexplained cardiomegaly Worsening cardiomegaly Unexplained congestive heart failure/gallop sounds Worsening congestive heart failure Pericarditis Pericardial rub Pericardial rub Pericardial effusion Pericardial effusion Miscellaneous Conduction disturbances or unexplained tachycardia Echocardiographic imaging Nuclear imaging Morphology evidence at surgery Histologic evidence at biopsy or pathology * Supportive evidence is required for the presence of acute rheumatic fever according to the Jones criteria. In patients with known rheumatic heart disease, acute rheumatic fever can be diagnosed with minor criteria along with evidence of antecedent streptococcal infection. These would be considered soft criteria. The significance of these methods is controversial. Endocarditis Endocardial inflammation most commonly affects the mitral and aortic valves, and the clinical diagnosis of rheumatic endocarditis is based on the demonstration of mitral or aortic regurgitation murmurs, or both. Mitral valve disease is seen in approximately 70% of patients, mitral and aortic valve disease occurs in an additional 25%, and isolated aortic valve disease occurs in 5% to 8%. Clinical tricuspid or pulmonary valve involvement is rare in the first attack of RF. The use of echocardiography has clarified the mechanism of valve regurgitation in RF. 33 Although mild-to-moderate mitral regurgitation is due to left ventricular dilatation with mild or no annular dilatation, more severe degrees of mitral regurgitation are associated with marked annular dilatation, chordal elongation, and anterior mitral leaflet prolapse. 34 Rarely chordae may rupture, to result in flail leaflets and severe regurgitation. Because mitral regurgitation frequently disappears on follow-up, 28,35,36 it is likely that a functional mechanism rather than a permanent structural alteration in the valve or annulus underlies the development of mitral regurgitation. Inflammatory changes in the aortic valves and the aortic ring result in aortic regurgitation; aortic valve prolapse may contribute occasionally. Myocarditis Myocardial involvement is generally associated with newonset cardiomegaly, an interval increase in cardiac size, or the development of congestive heart failure. 26,31,37 The left ventricular systolic function and myocardial contractility indexes are normal in patients with rheumatic carditis, and only minimal myocyte damage is pathologically seen in rheumatic carditis. It is has been thought that hemodynamically significant valvular lesions lead to the development of congestive heart failure. 37 Pericarditis Clinical rheumatic pericarditis occurs in up to 15% of patients during the acute stage of RF, and the presence of an evanescent pericardial friction rub in this setting is evidence of rheumatic carditis. The presence of pericarditis usually indicates severe carditis. 31 Rheumatic pericarditis is almost always associated with findings of valvular involvement. A pericardial rub can sometimes mask the underlying valvular murmurs. However, other causes need to be considered if no valvulitis-related murmur is audible after the resolution of pericarditis. 31 Rheumatic pericarditis is often associated with a mild-tomoderate serosanguineous effusion, and the development of pericardial tamponade is rare. Sydenham s Chorea Chorea is a late manifestation of RF that is characterized by a series of involuntary movements that commonly involve the face and extremities associated with emotional lability. 28 It commonly affects children between the ages of 7 and 14 years, and occurs more frequently in girls; it is rarely seen in adults. Chorea is often associated with carditis and subcutaneous nodules, but it appears several weeks after an acute attack of RF and when the acute manifestations have disappeared. The patients thus do not fulfill the Jones criteria at this time. The course of chorea is rather gradual as the patient appears increasingly nervous, becomes dysarthric, makes grimacing gestures, develops difficulty in writing, and shows characteristic purposeless movements of the arms and legs, which may be associated with muscular weakness. The chronic movements are exaggerated in effort or excitement but subside during sleep. Chorea is usually a selflimited condition and resolves without residual damage but the associated carditis can leave behind valvular damage. Skin Manifestations Subcutaneous nodules and erythema marginatum are two important skin manifestations of RF. Subcutaneous nodules occur late in the course of rheumatic fever. They are observed in up to 20% of patients, and their presence is usually associated with carditis. Subcutaneous nodules occur on bony prominences, vertebral spinous processes, or extensor tendons, and are painless. They usually appear in crops, are variable in size, and disappear within 2 to 3 months.

6 436 chapter 18 Erythema marginatum can be an early or a late manifestation. It occurs in fewer than 15% of patients and is present on the trunk and proximal extremities as a serpiginous, macular, nonpruritic, and evanescent rash. Clinical Diagnosis There is no single diagnostic test or pathognomonic sign that allows an absolute diagnosis of RF, and the condition is recognized through a constellation of signs and symptoms in the setting of recent GABHS pharyngitis. In 1944, Jones 38 described the clinical manifestations of RF and categorized them as major and minor. Since that time, the Jones criteria have been modified several times under the auspices of the American Heart Association. More recently, modifications have been suggested by the WHO 1 (Table 18.2). Various combinations of major and minor criteria are used for diagnosing ARF. The major manifestations include the presence of carditis, chorea, subcutaneous nodules, migratory arthritis involving large joints, and the skin rash known as erythema marginatum. The minor manifestations include fever, prolonged joint pains, prolonged electrocardiographic PR interval, laboratory indicators of inflammation, and acute phase reactants. An elevated antistreptolysin O (ASO) titer or other evidence of preceding streptococcal infection is considered a prerequisite. Although the Jones criteria remain the cornerstone of diagnosing ARF, they are continually changing to balance sensitivity/specificity, address different forms of presentation, accommodate a variable diagnostic armamentarium in different regions of the world, and reflect new information. The most current WHO iteration has many clinically important distinctions: (1) First attacks of RF and recurrent attacks in patients with no evidence of previous established RHD still need to adhere to the Jones criteria. (2) To diagnose recurrence in patients with established RHD requires only two convincing minor manifestations plus evidence of a recent streptococcal infection. (3) Evidence for recent streptococcal infection is not required in rheumatic chorea and insidious onset of clear rheumatic carditis. It should be remembered that these guidelines are general expert opinion and have not been prospectively tested for operating characteristics. Although Jones criteria provide an excellent set of guidelines for the diagnosis of RF, it is also important to remember that similar manifestations may be present in varying TABLE Jones criteria for diagnosis of acute fever* Major criteria Carditis Polyarthritis Chorea Subcutaneous nodules Erythema marginatum Minor criteria Arthralgia Fever Elevated erythrocyte sedimentation rate Positive C-reactive protein Leukocytosis Prolonged PR interval * Two major criteria or one major plus two minor criteria are required for the diagnosis of rheumatic fever. Supportive evidence of recent streptococcal infection is also required for all diagnoses. Chorea, indolent carditis, and poststreptococcal arthritis may not fulfill Jones criteria at the time of diagnosis. 59 degrees in other systemic illnesses, leading to the potential for misdiagnosis. For example, streptococcal infection is relatively common, and an elevated ASO titer indicates only previous infection. Similarly, arthralgia is prevalent in association with several viral syndromes, and carditis may occur as a consequence of Coxsackie B virus, Lyme disease, or Kawasaki s infection. The early manifestations of other collagen diseases, such as systemic lupus erythematosus, may also lead to confusion in diagnosis when they are associated with inflammatory abnormalities of the heart valves, particularly the mitral valve. Rheumatoid arthritis may produce aortic regurgitation, and inflammatory reaction within the pericardium or conduction system may result in pericarditis or heart block. There may be an erythema multiforme type of rash and laboratory evidence of an elevated erythrocyte sedimentation rate (ESR), anemia, and marked leukocytosis. For these reasons, rheumatoid arthritis is easily confused with RF. In a patient who has streptococcal infection and carditis, particularly with evidence of migratory polyarthritis, the diagnosis of RF should be assumed until proved otherwise. Laboratory Investigations Evidence of preceding streptococcal infection is a prerequisite for the diagnosis of RF. Because RF is a postinfectious immunologic complication, microbiologic evidence is limited, and the evidence for recent streptococcal infection is usually obtained with the antistreptococcal antibody tests. The most commonly used antibody assays include ASO and antideoxyribonuclease B (anti-dnase B), and other antibody tests such as hyaluronidase, streptokinase, and nicotinamide adenine dinucleotidase are occasionally used. 39 The antibody response to various streptococcal antigens develops within the first month and remains detectable up to 3 to 6 months after the infection. ASO titers are determined by an agglutination test or a hemolytic inhibition test, and in healthy adults the titers are usually less than 85 Todd units/ml, whereas school-age children can have ASO titers up to 170 U. Generally, an ASO level of more than 240 U in adults or more than 330 U in children is used for diagnosis, but a better diagnostic specificity is obtained by the demonstration of an interval increase in ASO in two serial samples. Because ASO titers rise and fall more rapidly, the anti-dnase B test can be performed if ASO is nondiagnostic. A rapid slide agglutination test that looks at antibodies against several (five) streptococcal antigens, the streptozyme test, has been proposed to improve the detection of streptococcal infection. The electrocardiogram may be normal in a patient with ARF. In patients who have cardiac involvement, ST-segment change may signal pericarditis, and repolarization abnormalities, including QT prolongation and T inversion, may occur in myocarditis. In addition, there may be associated arrhythmias with extrasystoles, supraventricular tachycardia, and atrioventricular blocks. First-degree atrioventricular block is commonly seen in patients with RF but is equally common in patients with or without carditis. The chest radiograph has been traditionally used to evaluate cardiomegaly and is an inexpensive way to study the evolution of the patient under treatment.

7 rheumatic fever 437 Echocardiography has become the tool of choice in diagnosis and monitoring cardiac structure and function. Current echocardiographic techniques were not available during many of the major RF epidemics, and thus its role has remained unclear. However, with newer data that are available, it might be time to selectively include this modality in the Jones criteria. An echocardiogram will quickly resolve whether a clinically undetectable murmur is truly absent and will protect patients with clinical carditis from being grouped with noncarditic patients, who have a more benign prognosis and require shorter secondary prophylaxis regimen. Indeed there are emerging data indicating that echocardiography can detect valve regurgitation more often than clinical exam alone 40 ; this advantage is greater with aortic valve involvement. More importantly, these kinds of data also suggest that echo detectable valve regurgitation can persist in a significant number of patients despite adequate prophylaxis, suggesting that echo detectable cardiac involvement might represent clinically important cardiac damage. A strategy to incorporate echocardiography into the Jones criteria is undoubtedly very appealing. 41 However, the Jones criteria are meant to have widespread applicability, and this transition to incorporating echocardiography should be achieved with multiple caveats. There is a concern that echocardiography may lead to the overdiagnosis of rheumatic carditis, and some investigators feel that the application of echocardiography should be somewhat dependent on the regional practice environment. Echocardiography should be routinely used to detect carditis in the developed world. It is widely available, first attacks are common, and the detection of carditis may be easy through echo. Subclinical cardiac involvement is quite common. Overdiagnosis, while possible, is avoided if strict criteria are applied for the exclusion of physiologic valvular regurgitation. 42 Even if echocardiography inappropriately detected subclinical carditis, serial echocardiographic studies will resolve the significance of such valve dysfunction. Therefore, the detection of subclinical carditis and even mislabeling a minority of patients with RF as having carditis for a short period of time until their clinical situation is resolved should not adversely affect the overall management strategy. On the other hand, the clinical situation is quite different in the developing world, 43 where the incidence of recurrent RF and the prevalence of RHD are very high and access to medical care is limited. First attacks are rarely witnessed, and patients present with recurrences and usually with established heart disease. Physical examination is the most commonly used method to detect patients with and without cardiac involvement. Moreover, there is some evidence, albeit controversial, that echocardiography in advanced disease does not demonstrate any incremental diagnostic benefit in endemic areas; this is probably due to a cumulative effect of multiple, clinical and subclinical recurrences. 33 In another study, most of the echo detectable carditis was also clinically detectable within a short period of follow-up. 44 Recurrences are common and medical records are sparse; thus one cannot be sure if trivial regurgitation is new carditis or residua of previous episodes in patients with streptococcal pharyngitis. Echocardiographic facilities are not widely available, and the cost and additional workload imposed with the universal use of echocardiography in RF episodes are likely to be enormous. Therefore, the detection of subclinical carditis in this population not only is very costly but also probably will not change the management strategy very much; none of the RF therapies available to date modify the natural history of carditis, and the initial period of prophylaxis is no different in patients without and with mild carditis. 43 In this population, the presence of RHD is a reason for lifelong prophylaxis, and echocardiography could be performed at the time of discontinuation of prophylaxis. The absence of heart disease at this time should allow the withdrawal of prophylaxis, whereas the presence of valvular disease should prompt lifelong prophylaxis. It is interesting to note that adding echocardiography to the initial workup, did not seem to make prophylaxis more rigorous in the developed world; only a small proportion of patients were taking prophylaxis on long-term follow-up. Finally, the natural history of echo detectable carditis is just being evaluated, and there may be merit in exercising caution 45 about making echocardiography the cornerstone of diagnosing carditis. Until there is a convincing body of data that demonstrates the need to detect subclinical carditis and the possibility of actually modifying its natural history, echo detectable carditis may divert scarce and valuable prophylaxis resources from more proven entities that need these urgently. Therefore, echocardiography should be selectively recommended for the investigation of RF in developing countries. 43 Of course, the role of echocardiography in the detection and management of established RHD is unquestioned in any population. Computed tomography or magnetic resonance imaging may also be useful in myocarditis but their role in RF remains unclear. 46 Endomyocardial biopsies have been performed in persons with acute rheumatic carditis. Aschoff nodules, which are pathognomonic features of rheumatic carditis, are observed in 40% of subjects, thereby offering a test of limited sensitivity. 25 However, because the biopsy results are mostly normal in patients with chronic RHD or noncarditic manifestations of RF, the specificity of the test is very high. In addition, various radionuclide imaging approaches have been evaluated in rheumatic carditis with variable success 47 ; these include imaging with indium 111 ( 111 In)-labeled antimyosin antibodies, radiolabeled leukocytes, and gallium 67 ( 67 Ga) scintigraphy. However, there needs to be more study about the role of such procedures, and they should be considered research at this time. Natural History A major problem with understanding the natural history of RF is that most data are old and have not been reevaluated in the current diagnostic and therapeutic milieu. It appears that the natural history of RF has changed significantly with the advent of prophylaxis, better recognition of antecedent streptococcal infections, social changes, and evolution in streptococcal virulence. Rheumatic fever appears to behave differently in the developing versus the developed world. Patients in the latter regions, probably due to conducive socioeconomic factors, demonstrate multiple recurrences and a particularly aggressive course. 48 However, it is heartening

8 438 chapter 18 that even in this situation, regular prophylaxis favorably modifies this bleak natural history. First attacks of RF in children characteristically occur between the ages of 5 and 15 years. Rheumatic fever rarely occurs in children younger than 2 years, and first attacks after the age of 40 years are also less common. Individuals who have RF are susceptible to recurrences of the disease, but this again diminishes with time. Rheumatic fever can recur with various manifestations at intervals of weeks, months, or years, with apparent inactivity between these episodes. The presence of congestive heart failure (CHF) is a seriously adverse prognostic indicator; failure of cardiomegaly and congestive cardiac failure to improve with treatment are associated with the worst prognosis. Patients with the initial syndrome of Sydenham s chorea have a lower mortality and morbidity rate. In patients who have no major valvular damage, the prevention of recurrent attacks leads to a significantly better prognosis with regard to overall survival and freedom from heart disease. If there is valvular involvement, the scarring process may lead to long-term impairment of valve function that progresses over 10 to 30 years, with various combinations of stenosis and regurgitation. Perhaps the most insidious of these is mitral stenosis, which may develop very late as long as 20 years after the onset of the acute infection often with no symptoms until the onset of atrial fibrillation. The onset of arrhythmias can be the beginning of rather rapid deterioration or thrombotic complications. Patients with valve dysfunction remain at risk for subacute bacterial endocarditis and should receive prophylactic antibiotics prior to procedures as indicated by consensus guidelines. Treatment The primary objective in the treatment of the patient with acute RF is the elimination of offending streptococci with appropriate antibiotic therapy; penicillin remains the agent of choice. There is a long list of choices for this purpose but it is important to remember that some of the more commonly used ones may not be as effective as others in preventing recurrent ARF. 49 The second objective of treatment of acute RF is to eliminate the inflammatory state, particularly that involving vital organs such as the heart. Salicylates, predominantly aspirin, have been used for many years as antiinflammatory agents in RF. They are very effective and the diagnosis of RF is suspect if high-dose salicylates do not significantly resolve joint pain and inflammation within 48 hours. Relatively high doses are needed: up to 8 to 10 g/day (100 mg/kg/day) for a period of 3 to 4 weeks. A gradual taper is recommended to avoid rebound worsening. Salicylates do not alter the natural history of the disease. Corticosteroids are used in patients with severe carditis and heart failure. Steroids rapidly suppress the toxic state, subside inflammation, help prevent the appearance of new murmurs, help murmurs disappear faster, allow faster resolution of pericardial effusions, and may be lifesaving in critical illness. 50 Similar to other therapies in RF, they do not alter the longterm natural history. 50 However, most of the studies are old, have serious methodologic problems, and have not studied combinations of current immunosuppressive therapies. A short course of steroids is commonly used in patients with severe carditis. Prednisone at 1 to 2 mg/kg/day is given for a period of 3 weeks with a tapering schedule once the acute symptoms resolve. There are no definitive end points for discontinuing antiinflammatory therapy in RF. General indicators include the absence of clinical symptoms and signs of rheumatic activity, in addition to normalization of acute-phase reactants, usually ESR. Too rapid reduction can be accompanied by a symptomatic rebound. The steroid taper is occasionally covered with salicylates to prevent a relapse. If heart failure continues to persist despite steroid therapy, surgical repair of mechanical lesions should be considered instead of prolonged trials with high-dose steroids. There is little data on newer forms of immunosuppressive therapy. It was long believed that surgery should not be undertaken during an acute inflammatory state, because earlier studies had showed increased surgical mortality rates in patients with acute RF. However, this is changing. Essop and associates 37 reported no deaths among patients with mitral or mitral and aortic valve replacement during active carditis, and surgery was associated with rapid and remarkable improvement, including a reduction in left ventricular dimensions. A subsequent series with a much longer followup period has shown that surgery during acute rheumatic carditis may be associated with a somewhat less favorable outcome of mitral valve repair, and surgical option during the acute episode should be reserved for subjects who are refractory in medical therapy. 51 In this study of Skoularigis and colleagues, 51 there was a relatively higher incidence of valve failure (27%), and the presence of acute carditis was the strongest predictor of reoperation. Cardiac surgery has been used with greater success in chronic RHD. It appears that there may be a significant degree of repairable valves, 52,53 and valve repair can be undertaken, albeit with some risk of reoperation. The third important objective in the treatment of RF is to prevent recurrences of rheumatic activity. 54 This is achieved by long-term antibiotic prophylaxis to prevent GABHS pharyngitis. A secondary prophylaxis program should begin during the acute episode of RF and is essentially based on the ability to prevent streptococcal pharyngitis. Rheumatic fever is a recurrent disease, and patients with carditis in previous attacks have a higher recurrence rate per streptococcal infection than those without previous carditis The likelihood of risk of recurrence per streptococcal infection may range up to 40% to 60% in young patients with established RHD, and every recurrence further damages the heart. Rheumatic fever recurrences can be prevented by chemoprophylaxis of streptococcal infections, which results in an eventual reduction in the prevalence of residual heart disease, 36,54 57 reduced need for operations, and a possible subsequent reduction in mortality rates due to RHD. The duration of prophylaxis is dependent on the anticipated risk of a recurrence of RF with each throat infection with Streptococcus, and is determined by the presence of carditis in the index RF episodes and the likelihood of acquiring streptococcal infection. The recurrence of RF is likely to be higher in patients with carditis or residual heart disease, multiple previous attacks, and younger age, whereas the risk decreases with the interval after the last attack. Streptococcal

9 rheumatic fever 439 TABLE Secondary prevention of rheumatic fever Agent Dose Mode Duration Benzathine penicillin G* 1.2 million U IM Every 4 weeks Penicillin V 250 mg b.i.d. PO Daily Sulfadiazine PO Daily <27 kg (60 lb) 500 mg 27 kg (60 lb) 1000 mg With penicillin and sulfa allergy Erythromycin 250 mg b.i.d. PO Daily * Use drug at room temperature and with procaine penicillin to reduce pain. Consider three times weekly in high-risk situations, including in Third World countries. May interfere with oral contraception. Avoid use in pregnancy. More effective than oral penicillin. infections are more common in schoolchildren, their parents, teachers or health personnel in contact with children, and persons living in closed quarters or in crowded housing. The recommendations for the choice of antibiotics and duration of prophylaxis are listed in Tables 18.3 and ,54 The need for prophylaxis should be reassessed periodically. In all situations, the decision to discontinue prophylaxis should be made after discussing the potential risks and benefits with the patients. While it is obvious that this program has the potential to significantly reduce morbidity with ARF, the success rates of optimally adhering to these guidelines has remained dismal. 58 This illustrates the immense number of challenges in controlling rheumatic fever. Streptococcal Vaccine The most effective way to reduce the global burden of RHD would be the development of an antistreptococcal vaccine. 59 The main target has been the streptococcal M protein, the principal virulence factor in group A streptococci since antibodies to M protein are long lasting and protective. 60 These approaches have been centered on either the type-specific N-terminal region (which protects against specific serotype) or the highly conserved carboxy-terminal region (which protects against multiple serotypes and also reduces colonization). In general vaccine strategies need to address the risk of cross-reactive epitopes (cross-reactivity against human heart and synovium), diverse M-type streptococci in a population, and the cyclical nature of prevalent organisms. 61 The N-terminal sequence (which is devoid of possible homology with human myocardial tissue) from all putative strains that could cause RF in a community can be used in a multivalent streptococcal vaccine. One of the current vaccines includes an octavalent antigenic peptide, 62 and the other contains recombinant M-protein fragments linked to Escherichia coli labile toxin. 63 The advantage of antibodies against the C-terminal region is that it is useful against multiple streptococcal strains. Non M-protein moieties have also been a focus of vaccine development. Intranasal immunization of mice with a defective form of the streptococcal C5a peptidase (which demonstrates excellent structural similarity in most streptococci) reduced the colonizing potential of several different streptococcal M serotypes. 64 C5 peptidase antibodies presumably help clearance of streptococci with the added advantage of a less likelihood of cross-reactive antibody formation. A similar benefit might accrue from including a streptococcal extracellular protease in a vaccine form. Mice passively or actively immunized with the streptococcal pyrogenic exotoxin B (SpeB) lived longer than non immunized animals after infection with group A streptococci. 65 There is a major push toward finding an effective vaccine; some vaccines are undergoing clinical testing, and an effective streptococcal vaccine is likely to be available soon. A successful vaccine could change the face of RF worldwide. TABLE Duration of secondary rheumatic fever prophylaxis* Risk of streptococcal infections Not high Category High <40 yrs of age 40 yrs of age RHD Lifelong Until 40 yr None History of carditis Until 40 yr of age Until 21 yr of age or 10 yr since last attack None and no RHD RF and no carditis Until 21 yr of age or 10 yr from last attack Until 21 yr of age or 5 yr since last attack None RF, rheumatic fever; RHD, residual rheumatic heart disease of any severity. Patients from developing countries, with large RF burden, should be considered at high risk for recurrent infections. * Each case is judged individually after considering the clinical situation and patient wishes. Modify prophylaxis in epidemic situations, especially if virulent streptococci reemerge. Should be at least 10 years since last attack and should not have history of multiple attacks. Use echocardiography if possible to prove or disprove RHD. Should be at least 10 years since last attack and should not have history of multiple attacks. Whichever is longer in duration.

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