Chapter 30 / Rheumatic Fever and Valvular Heart Disease

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Rheumatic Fever and Valvular Heart Disease Edmund A. W. Brice, MB ChB, PhD and Patrick J. Commerford, MB ChB INTRODUCTION

Rheumatic fever causes most cases of acquired heart disease in children and young adults worldwide. It is generally classified as a collagen vascular disease where the inflammatory insult is directed mainly against the tissues of the heart, joints, and the central nervous system. The inflammatory response, which is characterized by fibrinoid degeneration of collagen fibrils and connective tissue ground substance, is triggered by a throat infection with Group A -hemolytic streptococci (GAS). The destructive effects on cardiac valve tissue accounts for most of the morbidity and mortality seen in the disease through the serious hemodynamic disturbances produced.

ACUTE RHEUMATIC FEVER Epidemiology During the 20th century, the two major influences in the reduction of rheumatic fever incidence in many parts of the world were the advent of penicillin and improvements in socioeconomic conditions. At the turn of the 20th century the reported incidence of rheumatic fever in the United States was 100 per 100,000 population; by 1960 this had fallen to 45 per 100,000. The most recent US figures show that some regions have rates as low as 2 per 100,000. In stark contrast to these figures are those in the developing world,where rates as high as 1500 to 2100 per 100,000 have been reported in various areas of Africa, Asia, and South America. In Soweto, South Africa, a prevalence of rheumatic carditis of 1900 per 100,000 was reported in the early 1970s (1).

Pathogenesis The role of GAS in the genesis of rheumatic fever has been supported by a variety of clinical, epidemiologic, and immunologic observational studies. Pharyngeal infection with this organism is the only known cause of rheumatic fever. In situations of overcrowding, such as in schools or in military facilities, epidemics of streptococcal throat infection have resulted in approx 3% of those affected developing rheumatic fever (2). Group A -hemolytic streptococci have a variety of cell-wall antigens such as the M, T, and R proteins. It is the M-wall protein that is responsible for type-specific immunity and is widely regarded as determining streptococcal rheumatogenic potential. Patients with acute rheumatic fever are often found to have high titers of antibody to the M proteins. The currently accepted mode of development of acute rheumatic fever is that GAS pharyngitis leads to a host response to the GAS antigens, with cross-reactivity of the GAS antibodies with antigens in human tissues such as heart and brain (molecular mimicry) (3). This would explain the From: Essential Cardiology: Principles and Practice, 2nd Ed. Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ

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Brice and Commerford Table 1 Modified Criteria for Diagnosis of Acute Rheumatic Fever (6) Major

Minor

Carditis Chorea Polyarthritis Erythema marginatum Subcutaneous nodules

Fever Arthralgia Elevated ESR Elevated C-reactive protein Prolonged PR interval

frequent observation that, following pharyngeal infection, there is a 3-wk asymptomatic period and also the finding that rheumatic fever is rare in very young children. The peak incidence of rheumatic fever is between the ages of 5 and 18 yr. Host factors such as HLA subtypes have also been cited as possible explanations in the varying susceptibility to disease. Approximately 60–70% of patients worldwide are positive for HLA-DR3, DR4, DR7, DRW53, or DQW2 (4).

Clinical Presentation These is no test specific for the diagnosis of rheumatic fever; therefore, the diagnosis of a patient’s first attack of rheumatic fever is usually made by fulfilling the clinical criteria first formulated by Jones (5) and subsequently modified (6). These are divided into major and minor criteria and, if preceded by a GAS infection, two major or one major and two minor criteria are found, a diagnosis of rheumatic fever can be made (Table 1). Carditis is a pancarditis involving endo-, myo-, and pericardial tissues. Valvular involvement is frequent; if no evidence of this is found clinically despite myocarditis or pericarditis, rheumatic fever is unlikely. The mitral valve is most commonly involved, followed by the aortic valve, and gives rise to the frequent finding of regurgitant murmurs. A mitral systolic murmur, and occasionally even a mid-diastolic murmur (Carey-Coombs murmur: increased flow across the a mitral valve), detected during the course of an acute attack of rheumatic fever, do not necessarily indicate permanent valvular disease. An aortic early diastolic murmur rarely disappears and is evidence of established valve disease. Echocardiography is usually not required acutely and may give rise to overdiagnosis (7). As the progression to valvular stenosis through progressive scarring of the valve leaflets occurs gradually, early routine echocardiography seldom adds any information to that found clinically. Arthritis is symmetrical, migratory, and involves the larger joints such as the wrists, elbows, knees, and ankles. If a patient presents with joint symptoms and evidence of recent GAS pharyngitis, but has insufficient criteria for a diagnosis of rheumatic fever, poststreptococcal reactive arthritis must be considered. This may give rise to delayed carditis and, therefore, patients should be followed closely. Sydenham’s chorea, characterized by purposeless involuntary movements, incoordination, and emotional lability, is seen in about 20% of patients with rheumatic fever. It often presents 3 mo after the onset of the preceding GAS pharyngitis. Even without treatment, symptoms often resolve within 2 wk. Erythema marginatum, an erythematous macular rash of the trunk and proximal extremities, occurs in approx 5% of rheumatic fever cases. Lesions have pale centers with rounded or serpiginous pale-pink margins and are nonpruritic. They are transient and extremely difficult to detect, particularly in dark-skinned patients. Subcutaneous nodules are found in 3% of rheumatic fever cases and are painless, mobile, 0.5to 2-cm nodules on the extensor surfaces of joints, the occipital area of the scalp, and over spinous processes. Peritoneal involvement is rare but may simulate an acute abdomen, mimicking acute appendicitis in children.

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Often problematic is confirmation of the diagnosis of preceding GAS infection. Throat swab culture is positive in only approx 11% of patients at time of acute rheumatic fever diagnosis (8). A rapid streptococcal antigen test has also been utilized to confirm recent GAS infection. Another confirmatory test is the finding of a rising titer of antistreptococcal antibodies, either antistreptolysin O (ASO) or antideoxyribonuclease B (anti-DNase B). It is important to have a high level of suspicion of rheumatic fever in any patient presenting with a pyrexial illness, tachycardia, and a progressive symmetrical polyarthritis. While most patients are between the ages of 5 and 15 at first presentation, much older patients may occasionally develop acute rheumatic fever. Recurrence of rheumatic fever can occur at any age and must be distinguished from infective endocarditis.

Treatment Once the diagnosis has been made, it is customary for patients to be prescribed bed rest. Although at the time of presentation for rheumatic fever throat swabs are frequently negative for GAS, a 10d course of oral penicillin V or a single intramuscular injection of benzathine penicillin is empirically given to eradicate any GAS present. In order to minimize inflammatory damage to the affected tissues, often joint and cardiac, high doses of oral salicylates (100 mg/kg/d in divided doses) is cost-effective therapy. For patients with severe carditis or for those whose valve lesions may require early surgical repair, prednisone (2 mg/ kg/d) is often used instead of salicylates. The evidence for any real superiority of prednisone is weak but patients with carditis do appear to respond more rapidly to it (9). Duration of therapy is determined by clinical and laboratory evidence of resolution of inflammation. This is often achieved in milder cases after a month of salicylate therapy, although more severe cases may require 3 mo of steroid treatment and up to 5% of cases are still active at 6 mo. Heart failure, due to severe valve regurgitation, is the usual cause of death and, when it is resistant to antifailure therapy, may necessitate urgent valve replacement surgery, even in the presence of active carditis (10).

PRIMARY PREVENTION Prompt recognition and effective treatment of GAS pharyngitis can prevent the development of rheumatic fever, reducing both morbidity and mortality. Penicillin remains the most cost-effective agent in the treatment of GAS pharyngitis. Often a single intramuscular dose of benzathine penicillin (1.2 MU if 27 kg body weight) is effective. When compliance is not a concern an alternative oral regimen such as penicillin V (500 mg three times a day in adults) may be used. Erythromycin estolate (20–40 mg/kg/d in 2–4 daily doses) can be used in penicillin-allergic individuals. True primary prevention of GAS pharyngitis can only be achieved through prevention of the conditions of squalor, overcrowding, and socioeconomic deprivation that promote frequent attacks of GAS pharyngitis in communities. SECONDARY PREVENTION Recurrent attacks of rheumatic fever are common and can be reduced through the use of prophylactic antibiotics. Duration of secondary prevention must be individualized for patients and extended for those in poor socioeconomic conditions. Generally patients should, following their first attack of rheumatic fever, receive antibiotics until 21 yr of age or for at least 5 yr. Those with persistent evidence of carditis should receive prolonged therapy, some authors recommending treatment until age 40 or at least 10 yr after the attack. Antibiotic regimens whose efficacy is proven include 1.2 MU intramuscular benzathine penicillin every 3 wk (11). Oral therapy is often used for patients on warfarin anticoagulation and 250 mg penicillin V twice daily is recommended. Penicillin-allergic individuals may use 250 mg erythromycin twice daily. More recently, efforts have been made to develop vaccines incorporating recombinant M protein fragments in an effort to elicit a protective antibody response. Rabbits immunized with such

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Fig. 1. Simultaneous recording of left atrial (LA) and left ventricular (LV) pressure in a patient with severe MS before (left) and immediately after (right) balloon valvuloplasty. Shaded area indicates the gradient.

a vaccine have been shown to be highly immunogenic and evoke protective antibodies (12). Animal studies have thus shown the feasibility of this strategy and human studies are awaited.

MITRAL VALVE DISEASE Mitral Stenosis With the rare exception of congenital abnormalities, mitral stenosis (MS) due to abnormalities of the leaflets, commissures, and cusps of the valve is due to rheumatic fever (13). Some 40% of patients with rheumatic heart disease have combined mitral stenosis and mitral regurgitation and a quarter have pure mitral stenosis. Mitral stenosis is more common in females. The reason for this female predominance is unclear.

Pathology The rheumatic process affects the edges of the leaflets; resolution of the inflammatory process there is thickening, fibrosis, and fusion of the commissures. Involvement of the chordae tendineae results in thickening, fusion, and contraction with scarring extending down onto the papillary muscles. Dense fibrosis and calcification may reduce the normal delicate structure of the valve to a rigid, immobile, and funnel-shaped orifice.

Pathophysiology The normal adult mitral valve orifice area is 4–6 cm2. When MS reduces the orifice area to 2 cm2 a higher-than-normal pressure is required to propel blood from the left atrium to the left ventricle. When stenosis is more severe (1–1.5 cm2) a considerably elevated left atrial pressure is required to maintain a normal cardiac output even at rest, resulting in a pressure gradient across the valve (Fig. 1). The elevated left atrial pressure raises pulmonary capillary pressures, resulting in exertional dyspnea. Dyspnea usually first occurs with exercise, emotional stress, or infection that require an increased rate of flow across the mitral valve and hence a higher left atrial pressure. Patients with MS do not tolerate a tachycardia. An increase in heart rate shortens diastole proportionally

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more than systole and hence reduces the time available for blood flow across the mitral valve (14); the development of atrial fibrillation (AF) with a rapid ventricular rate may precipitate pulmonary edema in previously asymptomatic patients with MS. Pulmonary hypertension in patients with MS may result from passive backward transmission of the elevated left atrial pressure or organic obliterative changes in the pulmonary vasculature. Reactive pulmonary hypertension due to pulmonary arteriolar constriction triggered by left atrial and pulmonary venous hypertension may be important in some patients. Prolonged severe pulmonary hypertension results in dilation of the right ventricle and secondary tricuspid regurgitation.

Clinical Features HISTORY Subclinical or unrecognized attacks of acute rheumatic fever presumably account for the fact that fewer than half of all patients with MS clearly recollect the acute event. Dyspnea, which may be accompanied by cough and wheezing, is the major symptom of mitral stenosis. This is initially only exertional but with progression orthopnea and paroxysmal nocturnal dyspnea develop. Patients with severe mitral stenosis may tolerate modest impairment of ordinary daily activities but are at risk of developing frank pulmonary edema, which may be precipitated by exercise, chest infections, fever, emotional stress, pregnancy, intercourse, or the advent of atrial fibrillation. Classically several different kinds of hemoptysis are described as complicating mitral stenosis. • Sudden profuse hemorrhage (pulmonary apoplexy) results from the rupture of thin-walled dilated bronchial veins (15). It is more common early in the disease before bronchial veins thicken and are able to withstand the raised pressure. Often profuse and terrifying, it is rarely life-threatening. • Pink frothy sputum of pulmonary edema. • Blood-stained sputum associated with attacks of paroxysmal nocturnal dyspnea. • Pulmonary infarction, which is a late complication of long-standing MS associated with heart failure.

Thromboembolism is an important and life-threatening complication of MS. Systemic emboli occur in approx 20% of patients at some time. Emboli are more common in older patients with a low cardiac output, a large left atrial appendage, and atrial fibrillation. Embolism may, however, occur in patients with mild MS and may occasionally be the presenting feature. Cerebral, renal, and coronary emboli may occur and occasionally a large embolus may block the aorta at its bifurcation (saddle embolus). Unexpected systemic or cerebral emboli in a young patient should prompt a careful search for MS. Uncommon manifestations include chest pain indistinguishable from angina pectoris, which, in the absence of coronary disease, may be due to right ventricular or left atrial hypertension. Poorly explained, it resolves with successful treatment of the stenosis. Hoarseness caused by compression of the left recurrent laryngeal nerve by a dilated left atrium, lymph nodes, and dilated pulmonary artery occurs in isolated cases (Ortner’s syndrome). Severe untreated MS with pulmonary hypertension and right heart failure produces symptoms due to systemic venous hypertension with hepatomegaly, edema, and ascites.

PHYSICAL EXAMINATION The typical so-called mitral facies with pinkish-purple patches on the cheeks is rarely appreciated in dark-skinned patients in whom the disease is common. The pulse is normal in character but of small volume if the cardiac output is reduced. The venous pressure may be normal if pulmonary hypertension has not developed. When severe pulmonary hypertension is present a large “a” wave is found. Atrial fibrillation (AF) and tricuspid incompetence is associated with large “cv” waves and systolic hepatic pulsation. A typical feature on palpation is an easily palpable first heart sound (S1). Pulmonary hypertension produces a right ventricular lift and a palpable pulmonic closure sound (P2) in the left parasternal area.

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Fig. 2. Twelve-lead electrocardiogram in a patient with severe isolated mitral stenosis and pulmonary hypertension. It shows the combination of left atrial enlargement (P-wave broadened in lead II, biphasic in lead VI) and right ventricular hypertrophy (right axis deviation, dominant R in lead VI).

Auscultation is best performed with the patient turned into the left lateral position. The first heart sound is typically loud. This accentuation occurs when the anterior leaflet of the mitral valve remains pliable and is due to the abrupt crossover in pressure between left atrium and left ventricle at the onset of systole in mitral stenosis and the rapid acceleration of the closing leaflets (16). Normally the leaflets drift closed toward the end of diastole. In MS they are held open by the transmitral pressure gradient. Marked calcification or fibrosis of the leaflets attenuates the accentuation. In patients with pulmonary hypertension, P2 is accentuated. The mitral valve opening snap (OS) is heard only in patients with MS. Caused by sudden tensing of the anterior leaflet, it is best heard in the left parasternal area. The characteristic murmur is a low-pitched diastolic rumble best heard with the bell of the stethoscope and may be limited to the apex. Presystolic accentuation of the murmur occurs due to atrial contraction, which increases the gradient and flow across the mitral valve just prior to systole in patients in sinus rhythm. The auscultatory features of MS in obese and emphysematous patients are notoriously difficult. Simple bedside maneuvers (exercise) increase the heart rate and render the appreciation of the auscultatory features easier. Auscultation offers clues to severity of stenosis: The longer the murmur and the closer the OS is to the aortic component of the second sound (A2), the more severe the stenosis and mobility of the valve; a well-heard OS and loud, easily heard S1 imply that the anterior leaflet is mobile. The only important differential diagnosis to be considered is that of a left atrial myxoma, which may produce auscultatory features similar to those of MS. The characteristic inspiratory augmentation of the murmur of tricuspid stenosis should readily allow for its differentiation.

LABORATORY EXAMINATION Electrocardiography is relatively insensitive but may reveal characteristic changes in patients with moderate or severe mitral stenosis (Fig. 2). The chest radiograph usually shows an enlarged atrial appendage and left atrial enlargement will be visible on the left lateral view. Echocardiography (Fig. 3) both confirms the diagnosis by demonstrating thickening, restricted motion and doming of the anterior leaflet and provides vital information on the mobility of the anterior leaflet, the presence and severity of calcification of the valve, and involvement of the subvalvular apparatus, which determine selection of treatment. Color-flow Doppler echocardiography demonstrates the high-velocity jet entering the left ventricle (Fig. 4; see Color Plate 7, following p. 268) and allows quantitation of severity. Clinical evaluation and detailed echocardiographic examination including a Doppler study usually provides sufficient information to plan management without the need for cardiac catheterization, which can be reserved for patients in whom doubt remains about severity of associated mitral regurgitation, other valve lesions, or left ventricular function. Coronary angiography may be indicated in selected patients with chest pain syndromes or in those considered to be at risk of having coronary disease before elective valve replacement surgery.

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Fig. 3. Transthoracic echocardiographic images (parasternal long axis view) reveals left atrial (LA) enlargement and thickened domed anterior leaflet of the mitral valve (arrow).

Fig. 4. Color-flow Doppler echocardiography demonstrates the high-velocity jet entering the left ventricle (arrow). (See Color Plate 7, following p. 268.)

TREATMENT Medical treatment includes advice regarding lifestyle and pregnancy, long-term prophylaxis against recurrences of rheumatic fever if appropriate, antibiotic prophylaxis against infective endocarditis (although the risks are low), and prophylactic anticoagulation with warfarin if AF is present (sustained or paroxysmal). There is no clear evidence that warfarin anticoagulation is of benefit in patients in sinus rhythm who have not experienced an episode of systemic embolism. Diuretics and dietary sodium restriction reduce pulmonary congestion. -Blockers increase exercise capacity by reducing heart rate (17). Surgical treatment: Mechanical relief of obstruction may be obtained by closed mitral valvotomy, open mitral valvotomy, percutaneous balloon mitral valvuloplasty (PBMV), or mitral valve replacement. Selection and timing of the procedure requires clinical judgment based on knowledge of the patient’s symptoms, the severity of MS, and the risks of the procedure. PBMV has largely superseded surgical valvotomy in suitable patients with pliable leaflets and little or no significant calcification or mitral regurgitation (MR). A balloon catheter inserted via the femoral vein and a

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Fig. 5. An Inoue balloon catheter is positioned across the mitral valve. The indentation in the contrast-filled balloon as it ruptures the mitral valve commissures is evident.

transatrial puncture across the stenotic valve when dilated (Fig. 5) tears the fused commissures and partially relieves the obstruction. While palliative, PBMV preserves the patient’s own valvular apparatus and defers mitral valve replacement with its attendant risks. Periprocedural risk is low (1–3%), it can be performed as an emergency or in pregnant patients, and it provides excellent relief of symptoms. Severe MR may follow rupture of one of the leaflets. PBMV is usually recommended in patients with significant MS (mitral valve area