Rheumatic Fever


Fig. 2.1

Pathogenesis of acute rheumatic fever (ARF). In susceptible individuals, ARF develops as a delayed, noninfectious consequence of prior streptococcal pharyngitis. The initial event is a febrile illness due to an episode of pharyngitis produced by a group A β hemolytic streptococcus. During an asymptomatic interval, T lymphocytes become activated by streptococcal antigens and B lymphocytes produce antistreptococcal antibodies. The activated T cells and anti-streptococcal antibodies cross-react with epitopes on the host tissues. The result is a febrile multisystem disorder known as ARF. The protean manifestations of ARF include erythema annulare, migratory polyarthritis, Sydenham’s chorea, and pancarditis. The pancarditis manifests as fibrinous pericarditis, granulomatous myocardial lesions known as Aschoff bodies , and inflammation with sterile vegetations on the cardiac valves. ARF may be a limited illness, and many of the organ manifestations may be reversible, but it can have permanent sequelae, the most important of which is chronic rheumatic heart disease due to progressive damage and dysfunction of cardiac valves



Only a few individuals with GABHS infection develop RF [8, 9], and the genetic makeup of the host may affect 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. Belonging to certain racial groups (e.g., Samoans in Hawaii, Maori in New Zealand) and a history of previous episodes of RF increase one’s susceptibility to streptococcal RF after pharyngitis . Another factor may be differences in the hosts’ ability to mount a vigorous antibody response, which correlates with the occurrence of ARF. Familial or genetic susceptibility to RF has been proposed [4, 10, 11]. Several candidate gene studies [12], twin studies [13], and two genome-wide association studies [14, 15] provide further evidence for genetic susceptibility, and offer insights into the potential pathways through which genetic susceptibility may mediate the predisposition to develop ARF and RHD.


Among the various serotypes of GABHS , some appear more likely to initiate ARF (M-types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29), whereas others 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 [16]. In general, the RF-causing strains tend to be rich in M protein, provoke an intense M-type-specific immune response, and probably share epitopes with human tissue.


Mechanisms of Damage


Despite some claims of direct injury by streptococci, viruses, or toxins, most data suggest that RF occurs as a result of autoimmune injury. Antibodies (cross-reactive and polyspecific) that react to antigens shared between streptococci and human tissue (molecular mimicry) are thought to underlie this process (Fig. 2.1). Rheumatogenic streptococci contain multiple antigenic determinants that partially mimic normal human tissue antigen [9]. Thus, the hyaluronate capsule, the streptococcal membrane, and the M-proteins share similarity with valve glycoproteins, myocardial sarcolemma, and cardiac contractile proteins, respectively. After 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 antigens. The type of damage is 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 [17], and this cross-reaction is thought to mediate valve damage; indeed, plasma levels of such antibodies are increased in patients with rheumatic heart valve disease [18].


Breakdown of tolerance is an important component of the pathogenesis of ARF. The M-protein epitopes not only can trigger heart cross-reactive antibodies and T-cell responses but also can act as superantigens [19]. This might explain the widespread immune response overriding the histocompatibility barrier. Both humoral and cellular immune responses are more vigorous in patients with ARF than in healthy individuals and might be related to the superantigenic property of streptococcal M protein. Significant T-cell infiltration is also observed in the valvular tissue, and T cells isolated from the valvular tissue of patients with RHD respond to streptococcal M5 protein and also cross-react with cardiac myosin [20, 21]. This homology with cardiac myosin can be expected to decrease tolerance and may enhance T-cell-mediated inflammatory damage [22]. The characteristic pathological findings (see below) suggest that the primary focus of ARF-induced damage is endothelium and subendothelial and perivascular connective tissue.


Both humoral and cell-mediated immune responses contribute to valve damage in ARF [4]. Binding of cross-reactive antibodies at the endothelial surface of the valve leads to upregulation of VCAM-1, which in turn induces adherence and infiltration by activated CD4 T cells and B lymphocytes [23]. Inflammatory cytokines released through a Th 1 immune response cause local tissue damage [24]. Binding to other antigens such as vimentin, laminin, and collagen cause further injury, which heals by neovascularization and fibrosis, resulting in the valve lesions typical of RHD [4].


The characteristic pathological findings (see below) suggest that the primary focus of ARF-induced damage is endothelium and subendothelial and perivascular connective tissue. Recently, a streptococcal M protein N-terminus domain has been shown to bind to the CB3 collagen type IV [25]. This binding may initiate an antibody response to the collagen and result in inflammation of the ground substance. Because these antibodies do not cross-react with M proteins, failure of the immune system and molecular mimicry may not be involved in their pathological effects. This alternative pathogenetic mechanism shares similarity with collagen involvement in both Goodpasture syndrome and Alport syndrome .


Pathology


The cardiac and non-cardiac tissues differ in how they react to ARF [26, 27]. 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. Fibrinoid exudates frequently line the membranes. The blood vessels in the articular and periarticular areas are often inflamed and show infiltration by 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 (resulting in pancarditis). The pericarditis is typically fibrinous (Fig. 2.2).

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Fig. 2.2

Acute fibrinous pericarditis typical of ARF and other rheumatic diseases. The epicardial surface of the heart is covered with shaggy fibrinous exudates


A fundamental pathological process in ARF is damage of the collagenous matrix of the cardiac and extracardiac tissue that elicits a granulomatous reaction called an Aschoff body . The process has early, intermediate, and late phases. The early and intermediate phases are characterized by fibrinoid necrosis. This is followed by a granulomatous reaction leading to the formation of the pathognomonic Aschoff body (Figs. 2.3 and 2.4) [28]. The Aschoff body consists of a central area of fibrinoid necrosis surrounded by cells of histiocytic-macrophage origin (Anitschkow cells), which show a typical owl’s eye-shaped nucleus. These cells are usually found in the subendocardial or perivascular regions of the myocardium. There is surprisingly little histopathologic damage to the myocardium, even in patients with florid clinical carditis and heart failure [29, 30]. Myocyte necrosis is uncommon, and the cellular infiltrate is confined to the interstitium. This explains why even patients with frank rheumatic myocarditis do not have troponin leaks [31]. The conduction system shows little pathology, even in patients with clinical conduction defects. The valves are inflamed and thickened during the acute stage of the rheumatic activity. The surface of the valves develop small, sterile vegetations, or verrucae—particularly along the edges of the leaflets (Figs. 2.5 and 2.6)—that are not associated with thromboembolic sequelae. The inflammation is followed by a repair process involving ingrowth of blood vessels (neovascularization) and deposition of collagen (Fig. 2.7). A mild degree of inflammation leads to fusion of the cusps, whereas more severe inflammatory reaction extends to involve the chordae tendineae. This can result in early mitral or tricuspid regurgitation, caused by annular dilatation and leaflet prolapse. The scarring process typically occurs gradually, such that mitral and/or aortic regurgitation may not be initially manifest and then present months to years later clinically. Mitral and, rarely, aortic stenosis are late sequelae that result from scarring and inflammatory fusion of leaflet cusps (Fig. 2.8).

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Fig. 2.3

Aschoff body in the myocardial interstitium consisting of a focus of granulomatous inflammation composed of T lymphocytes, occasional plasma cells, and plump activated macrophages called Anitschkow cells. The myocardial inflammation in ARF begins as foci of fibrinoid necrosis that evolve into foci of granulomatous inflammation. The cellular inflammation is confined to the interstitium, usually in a perivascular location. Myocardial necrosis is not seen even in patients with florid carditis and heart failure. The myocardial failure appears related to humorally mediated myocardial dysfunction leading to cardiac dilatation and mitral regurgitation due to dilatation of the mitral annulus. H&E stain; medium magnification


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Fig. 2.4

Aschoff body with mononuclear Anitschkow cells and binucleate Aschoff cells. The nuclei of the Anitschkow and Aschoff cells are activated macrophages with central bars of chromatin, giving them an “owl-eye” appearance in cross-section. The Aschoff bodies are considered to be pathognomonic for the diagnosis of ARF. H&E stain; high magnification


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Fig. 2.5

Acute rheumatic valvulitis , mitral valve. Minute, translucent nodular vegetations called verrucae, 1–3 mm in diameter, are located along the lines of closure on the inflow (atrial) side of the leaflets. The nodules represent foci of fibrinoid necrosis and thrombosis devoid of micro-organisms. Systemic lupus erythematosus (SLE) also may exhibit a similar but distinctive type of sterile vegetative endocarditis. The Libman-Sacks endocarditis (LSE) caused by SLE has small or medium-sized vegetations on either or both sides of the valve leaflets. Both types of rheumatic vegetative endocarditis are distinct from the patterns of vegetative endocarditis seen in non-bacterial thrombotic endocarditis (NBTE) and infective endocarditis (IE) . Reproduced with permission from: McAllister HA Jr., Buja LM, Ferrans VJ. Valvular heart disease: anatomic abnormalities. In: Willerson JT, Cohn JN, Wellens HJJ, Holmes DR, Jr., Editors. Cardiovascular Medicine, third edition. London: Springer Verlag, 2007, p. 372 (Fig. 14.6)


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Fig. 2.6

Typical verrucae of ARF, composed of sterile fibrin-rich thrombus. There is surface necrosis and lymphohistiocytic inflammation in the underlying valve tissue. H&E stain; high magnification


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Fig. 2.7

Histology of mitral valve in healing phase of ARF. The autoimmune injury with necrosis, inflammation, and thrombosis triggers a repair process involving granulation tissue formation with the ingrowth of blood vessels and deposition of collagen. Thick-walled blood vessels that persist in the atrialis layer of the valve leaflets are recognized as neovascularization of the valve, as shown here. Contraction of the fibrous tissue leads to retraction of the leaflets. Organization of thrombus formed at the lateral margins of the leaflets leads to commissural fusion. H&E stain; medium magnification


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Fig. 2.8

Chronic rheumatic heart disease . The heart manifests sequelae after a single bout or recurrent episodes of ARF. The fibrinous pericarditis resolves with residual pericardial adhesions. Healing of the granulomatous Aschoff bodies results in areas of perivascular fibrosis. The repair of the acute injury to the valves results in variable combinations of fusion of chordae tendineae, fibrous thickening of leaflets or cusps, neovascularization, and commissural fusion. Over a period of months to years, progressive distortion of valvular architecture and function occurs as a result of chronic turbulence of flow across the valves and other mechanical factors rather than to ongoing autoimmune inflammatory insult. Secondary dystrophic calcification adds to the distortion of the valvular anatomy and can obliterate the characteristic feature of neovascularization. The end result is clinically significant stenosis, regurgitation of the mitral and/or aortic valves, or both, which is recognized clinically as chronic rheumatic heart disease. Chronic rheumatic heart disease shares similar pathologic features with the valve disease seen in systemic lupus erythematosus. The generic designation for the characteristic pathology is post-inflammatory valvulopathy


Clinical Features


Joint Symptoms


Arthritis is the earliest manifestation of RF and frequently brings the patient to clinical attention [32]. 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 hands and feet may be seen; the hips, spine, and axial joints are rarely affected. The joints are swollen, hot, red, and tender. The joints are inflamed at different times and for various intervals, imparting a migratory character to joint pain. Aseptic monoarthritis may be frequent in endemic countries [33]. Arthritis usually resolves in 3–4 weeks, even without treatment, but it responds instantly to aspirin therapy and does not lead to permanent damage. Arthralgia without objective signs of inflammation is common in younger patients with carditis, particularly during rheumatic recurrences and in RHD patients in developing countries [34]. Some forms of polyarthritis after streptococcal pharyngitis may represent a reactive phenomenon. Post-streptococcal arthropathy is characterized by recurrent, severe, prolonged polyarthritis that is not very responsive to nonsteroidal anti-inflammatory agents. Although other manifestations of RF are not associated with arthropathy, some patients end up with residual heart disease [35]. Prophylaxis against reactive arthropathy remains similar to that for patients with RF, but few data are available to support definitive recommendations.


Cardiac Involvement


Carditis is the only manifestation of RF that results in permanent deformity [36]. Cardiac involvement in RF has been reported in nearly one-third of almost all cases in various studies and in up to one-half of cases in a prospective series [37]. Clinical carditis was seen in 72% of patients in a resurgence of RF in Salt Lake City [5], which is similar to the prevalence in the early twentieth century in the United States [38]. Subclinical carditis is being increasingly detected with modern imaging methods; valvular regurgitation can be documented in such cases with the use of echocardiography [39, 40] in 70–90% of all patients with ARF. Active rheumatic carditis can present in several ways, including subclinical cardiac involvement, acute or even fulminant congestive heart failure, and, occasionally, chronic heart failure. Younger patients often present with carditis, whereas older patients more commonly have joint involvement [32]. Although episodes of carditis occur less frequently in many older patients, they present more often with unexplained worsening of congestive heart failure. The clinical findings may be suggestive of pericarditis, myocarditis, and valvulitis. The guidelines for the diagnosis of rheumatic carditis are summarized in Table 2.1.


Table 2.1

Acute rheumatic carditis a





























Criteria

First attacks

Recurrences

Valvulitis


New-onset apical systolic murmur or aortic regurgitation murmur


Carey-Coombs murmur

Change in murmur


New-onset murmur


Myocarditis


Unexplained cardiomegaly


Unexplained congestive heart failure/gallop sounds

Worsening cardiomegaly


Worsening congestive heart failure


Pericarditis


Pericardial rub


Pericardial effusion

Pericardial rub


Pericardial effusion


Miscellaneous

Conduction disturbances or unexplained tachycardiab


Echocardiographic imaging findingsc


Nuclear imaging findingsc


Morphologic evidence at surgery


Histologic evidence at biopsy or pathology examination

  


aSupportive evidence is required for the diagnosis 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


bThese would be considered soft criteria


cThe validity 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 identifying mitral or aortic regurgitation murmurs. 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 5–8%. 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 [39]. 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 [41]. Rarely, chordae rupture and result in flail leaflets and severe regurgitation. Because mitral regurgitation frequently resolves on follow-up [32, 42, 43], 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 contributes occasionally.


Myocarditis


Myocardial involvement is generally associated with new-onset cardiomegaly, an interval increase in cardiac size, or the development of congestive heart failure [30, 36, 44]. The left ventricular systolic function and myocardial contractility indices are normal in patients with rheumatic carditis, and histopathological examination reveals only minimal myocyte damage. Some evidence suggests that hemodynamically significant valvular lesions lead to the development of congestive heart failure [44].


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 such patients is evidence of rheumatic carditis. Detectable pericarditis usually indicates severe carditis [36].


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 pericarditis resolves [36]. Rheumatic pericarditis is often associated with a mild-to-moderate serosanguineous effusion, and the development of pericardial tamponade is rare.


Sydenham Chorea


Sydenham chorea is a late manifestation of ARF that is characterized by a series of involuntary movements that commonly involve the face and extremities and are associated with emotional lability [32]. It commonly affects children between the ages of 7 and 14 years and occurs more frequently in girls; it is rarely seen in adults. The chorea is often associated with carditis and subcutaneous nodules, but it appears several weeks after an acute attack of ARF, when the acute manifestations have disappeared. The patients thus do not fulfill the Jones criteria at this time. The course of chorea is 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 during effort or excitement but subside during sleep. The chorea is usually a self-limited 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 appear late in the course of RF. 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 2–3 months.


Erythema marginatum can be an early or a late manifestation. It occurs in fewer than 15% of patients and appears on the trunk and proximal extremities as a serpiginous, macular, non-pruritic, and evanescent rash.


Clinical Diagnosis


There is no single diagnostic test or pathognomonic sign that allows an absolute diagnosis of RF; rather, the condition is recognized through a constellation of signs and symptoms in patients with recent GABHS pharyngitis . In 1944, Jones [45] described the clinical manifestations of RF and categorized each of them as major or minor. Since that time, the Jones criteria have been modified several times and by the WHO [3, 46] (Table 2.2). The most recent modifications suggested by the AHA were published in 2015 [47].
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Apr 23, 2020 | Posted by in CARDIOLOGY | Comments Off on Rheumatic Fever

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